Meeting without Britain, the other 27 member countries will endorse a declaration of intent for the next decade, on the Capitoline Hill where six founding states signed the Treaty of Rome on March 25, 1957.
EU President Donald Tusk and the prime ministers of Italy and Malta greeted the leaders as they arrived at the Renaissance-era Palazzo dei Conservatori next to the Forum, for a ceremony long on pomp and short on real politics.
"There will be a 100th birthday of the European Union," European Commission chief Jean-Claude Juncker said in an interview with German television ahead of the summit.
The leaders had the words of Pope Francis ringing in their ears, after he warned on the eve of the summit that the crisis-ridden bloc "risks dying" without a new vision.
The Argentine pontiff urged the leaders at a personal audience in the Vatican City on Friday to show solidarity as an "antidote" to populist parties whose popularity has surged in Europe.
The White House congratulated the EU overnight on its 60th birthday, in a notable shift in tone for President Donald Trump's administration, whose deep scepticism about the bloc has alarmed Brussels.
"Our two continents share the same values and, above all, the same commitment to promote peace and prosperity through freedom, democracy, and the rule of law," the White House said in a statement.
'Europe our common future'
The 27 are set to hear a series of speeches urging unity and leadership from Tusk, Juncker, Italian PM Paolo Gentiloni and Maltese premier Joseph Muscat, whose country holds the EU's rotating presidency.
But British Prime Minister Theresa May's absence, four days before she launches the two-year Brexit process, and a row over the wording of the Rome declaration underscore the challenges the EU faces.
Security is tight with snipers on rooftops, drones in the skies and 3,000 police officers on the streets following an attack this week in London claimed by the Islamic State (IS) group.
The Rome Declaration that the leaders will sign proclaims that "Europe is our common future", according to a copy obtained by AFP.
But mass migration, the eurozone debt crisis, terrorism and the rise of populist parties have left a bloc formed from the ashes of World War II
searching for new answers.
The leaders are deeply divided over the way forward almost before they have started.
Polish Prime Minister Beata Szydlo only agreed to sign the declaration at the last minute, after bitterly opposing a reference to a "multi-speed" Europe favoured by powerhouse states France and Germany.
Poland, central Europe's largest economy, is concerned that as one of nine of the EU's current 28 members outside the eurozone, it could be left behind should countries sharing the single currency push ahead with integration.
Greece, the loudest voice against the austerity policies wrought by its three eurozone bailouts, meanwhile insisted that the document should mention social policies.
The aim of the summit was to channel the spirit of the Treaty of Rome that Belgium, France, Italy, Luxembourg, The Netherlands and West Germany signed six decades ago to create the European Economic Community (EEC).
The treaty was signed in the Horatii and Curiatii hall of the Palazzo dei Conservatori, one of the Renaissance palaces that line the Michelangelo-designed Capitoline Square, and the political and religious heart of the Roman Empire in ancient times.
Police in the Eternal City will be on the alert not only for lone wolf attackers in the wake of the British parliament attack on Wednesday, but also violent anti-Europe demonstrators.
Around 30,000 protesters are expected to take part in four separate marches -- both pro- and anti-Europe -- throughout the day. Police plan to stop all traffic and declare a no-fly zone.
A grassroots movement led by former Greek finance minister and leading austerity critic Yanis Varoufakis will launch a new manifesto, with Varoufakis warning that the EU is "disintegrating" so fast it might not last another decade.