In the immediate aftermath of the British vote, seven years of potentially bitter divorce negotiations between Brussels and London loom.
The remaining EU countries will likely be keen to move ahead. France and Germany, the main EU heavyweights, have already been working on a joint plan for the future.
But with Berlin and Paris at loggerheads over future integration of the eurozone, any plan is likely to be a modest affair that deals only with issues such as security and defence.
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Even without Britain in the club, the drift away from "ever closer union" and federalism is likely to increase, with growing talk of a "two-speed Europe" that allows states opt-outs from key rules.
One major step could be making membership of the euro non-compulsory, which would help Poland, which appears to have no intention of joining the single currency but is officially meant to.
The main fear in many European capitals is that either way, the result could trigger a domino effect of referendums in other countries.
French far-right leader Marine Le Pen on Tuesday urged all EU states to follow Britain's example, and eurosceptics in the Netherlands, Denmark and Sweden have made similar calls for referendums.
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Vivien Pertusot, Brussels-based analyst with the French Institute of International Relations (IFRI), said the EU was likely to survive but be weakened.
"Institutions rarely die," he told AFP. "Maybe there will not be disintegration, but a loss of relevance. The EU will lose, bit by bit, its centrality for all the most political projects."
The danger for the EU is that even after if makes changes following the British referendum, it will still not be able to quell the forces of history tearing it apart.
"The EU is in a negative spiral," Janis Emmanouilidis, director of studies at Brussels-based think tank European Policy Centre, told AFP.
The question of what could replace the EU if it does collapse is even more vexed.
"It might sound as if yes, this story has ended, a new one has began, but that's not not easy. Especially after the experience of failure," said Emmanouilidis.