Britain's decision to quit the European Union could send damaging shockwaves through the bedrock Anglo-American "special relationship," raising questions about London's willingness and ability to back US-led efforts in global crises ranging from the Middle East to Ukraine.
The loss of the strongest pro-US voice within the 28-nation bloc, as a result of the "Brexit" referendum, threatens to weaken Washington's influence in European policymaking and embolden Russian President Vladimir Putin to further challenge the West, analysts and former diplomats say.
The British referendum on Thursday, widely seen as reflecting an increasingly nationalistic and inward-looking public, also risks the splintering of the United Kingdom itself, which could further reduce its role and stature in world affairs.
Britain's departure - which is not immediate and must be negotiated with the EU - could present the next US president with a decision on whether to turn to other key European partners like Germany and France, essentially downgrading a special US bond with London forged in World War Two.
Ivo Daalder, a former US ambassador to Nato and the president of the Chicago Council on Global Affairs, said Britain's ability to press its views and policy preferences with its European allies and within Nato, where it provided strong political backing to the United States, will be diminished.
"You clearly have a much weaker Britain whose sway in European capitals is lessened by the vote," Daalder said. As a result, he said, the United States likely will have to work harder to maintain trans-Atlantic and European unity.
Anything that divides Europe, he added, "is a win for Russia because that has been a policy of Putin and of Russia."
A US intelligence official, speaking on condition of anonymity, said: "This is certain to encourage the Russians to continue and probably intensify their campaign of supporting far-right nationalist movements in Western and Eastern Europe as part of their effort to neuter Nato."
Phil Gordon, a former senior foreign policy adviser to Obama, expressed concern that Europe will become inwardly focused on Britain's departure and independence movements on the continent, leaving the United States to shoulder more of the international burden.
"The more time it spends on doing that, the more resources it spends on coping with the consequences of that, the less time and money and political capital it is going to have to help us with global challenges," he said.
The administration of President Barack Obama was rattled by the stunning turn of events, including turmoil in world financial markets and British Prime Minister David Cameron's subsequent resignation announcement.
British officials sought to reassure their US counterparts that Brexit would not portend a withdrawal from world affairs, a US official said. Some of those officials may not survive the change of leadership or further British political upheavals that could be spurred by the vote.
Rebuke to Obama
While Obama insisted on Friday that Britain would remain an "indispensable partner," the outcome of the referendum delivered a clear rebuke to the US president, who made an unusually strong intervention into British politics against "Brexit" during a visit to London in April.
Britain's vote to leave the EU threatens not only Obama's security efforts across the globe but the US economic recovery and the international trade agenda he is pursuing in his final seven months in office.
A similar mix of US populist anger and anti-establishment sentiment has fueled the rise of Donald Trump as presumptive Republican nominee in the November US presidential election.
"The drivers of Brexit are the same as the drivers of nationalist movements in western Europe and the US," Clifford Young, President of Ipsos Public Affairs in the United States, told Reuters.
Cameron has cooperated closely with Obama in the security sphere. Britain has been a major military player in US-led campaigns against Islamic State militants in Syria and Iraq, an active ally on the ground in Afghanistan and a strong supporter of sanctions against Russia over its role in Ukraine's separatist conflict.
Heather Conley, director of the Europe Program at the Center for Strategic and International Studies in Washington, said Britain's divorce from the EU, which could take up to two years, would now be "an all-consuming process" that could distract it from such efforts.
"There's just not going to be an enormous amount of attention of policy bandwidth given to the migration crisis, fighting ISIS, or focusing on continued ceasefire violations in Ukraine and maintaining sanctions against Russia," she said.
"It comes down to when we need the UK and its leadership, whether in the Security Council or Nato, its attentions will be focused domestically," she said.
Richard Haass, president of the Council on Foreign Relations, called Brexit - which dealt the biggest blow to the European project of unity since World War Two - "a cloud without a silver lining."
"I'm not suggesting that we're about to return to a situation of conflict in Europe," he said. "But I'm wary that it will tear from the fabric of prosperity and stability."
While US-British intelligence sharing - one of the closest relationships of its kind in the world - is expected to withstand the political turmoil, some experts said counterterrorism cooperation with European partners could suffer at a time when Islamic State has targeted European capitals.
"It will make cooperation in Europe on counter terrorism harder as most of the former British intelligence chiefs predicted before the vote," said Bruce Riedel, a former CIA official now at the Brookings Institution think tank in Washington.
But Michael Morell, a former acting CIA director, rejected that view, saying counterterrorism cooperation "is too important to let politics of any kind affect it."
Adding to US concerns is the threat by Scottish nationalists to mount a new referendum on independence for Scotland, where nearly two-thirds of voters voted to stay in the EU. In addition, Northern Ireland's deputy leader Martin McGuinness called for a vote to unite the two sides of the Irish border.
The break-up of the United Kingdom would raise questions whether it should retain its veto in the United Nations Security Council, where it has been a mostly reliable supporter of US initiatives.