Angry mobs of Islamists battled secular protesters with fists, rocks and firebombs in the streets around the presidential palace for hours Wednesday night in the first major outbreak of violence between political factions here since the revolt against then-President Hosni Mubarak began nearly two years ago.

Three senior advisers to Mr. Mubarak’s successor, Mohamed Morsi, Egypt’s first freely elected president, resigned during the clashes, blaming him for the bloodshed, and his prime minister implored both sides to pull back in order to make room for “dialogue.”

The scale of the clashes, in an affluent neighborhood just outside Mr. Morsi’s office in the presidential palace, raised the first doubts about Mr. Morsi’s attempt to hold a referendum on Dec. 15 to approve a draft constitution approved by his Islamist allies over the objections of his secular opposition and the Coptic Christian church.

Periodic gunshot blasts could be heard at the front lines of the fight, and secular protesters displayed birdshot wounds and pellets. But it could not be determined whether the riot police or Islamists or the opposition had fired the guns.