The UK has regretted "turning its back" on Europe in the past, the PM said, arguing the EU had "helped reconcile" countries and maintain peace, the BBC reports.
Was leaving the union a "risk worth taking," Mr. Cameron asked.
The PM, who was introduced by former Labour foreign secretary David Miliband, argued the EU - with Britain in it - had helped bring together countries that had been "at each others' throats for decades."
He warned the peace and stability Europe has enjoyed in recent years could not be guaranteed, saying leaving risked "the clock being turned back to an age of competing nationalism in Europ."
Read alsoObama: Britain must vote to remain in EUWhile Europe has largely been at peace since 1945, Mr. Cameron said it was barely two decades since the Bosnian war while, more recently, Russia has been at war with Georgia and Ukraine.
"Can we be so sure that peace and stability on our continent are assured beyond any shadow of doubt? Is that a risk worth taking? I would never be so rash as to make that assumption," he said.
Mr. Cameron argued "isolationism has never served this country well."
Meanwhile, in his own speech on Europe, ex-London mayor Boris Johnson said the PM's argument "grossly underestimates the way Europe has changed" as well as the role of NATO.
He said the EU itself and its "anti-democratic tendencies" were in fact "a force for instability and alienation."