By Shaimaa Fayed and Yasmine Saleh
Waving national flags and chanting "Get out!", a crowd of more than 200,000 had massed by sunset on Cairo's central Tahrir Square in the biggest demonstration since the 2011 uprising that overthrew Mursi's predecessor, Hosni Mubarak.
"The people want the fall of the regime!" they shouted, echoing the Arab Spring rallying cry that brought down Mubarak - this time yelling it not against an ageing dictator but against the first elected leader in Egypt's 5,000 year recorded history.
Many bellowed their anger at Mursi's Muslim Brotherhood, accused of hijacking the revolution and using electoral victories to monopolize power and push through Islamic law.
Others have been alienated by a deepening economic crisis and worsening personal security, aggravated by a political deadlock over which Mursi has presided.
As the working day ended and 38 Celsius (100 Fahrenheit) heat eased, more protesters converged through the eerily deserted streets of the shuttered city centre, while smaller crowds protested in several other areas of the capital.
The veteran leaders of Egypt's secular, liberal and left-wing opposition, including former chief of the U.N. nuclear watchdog Mohamed ElBaradei and leftist presidential candidate Hamdeen Sabahi, joined protest marches in Cairo.
A Reuters journalist said hundreds of thousands of anti-government protesters marched through the Mediterranean port of Alexandria, Egypt's second city, and a military source reported protests in at least 20 towns around the country.
Mursi, an engineering professor propelled to power by the Muslim Brotherhood, was monitoring events from the heavily guarded Qubba presidential palace, where an official spokesman appealed for the demonstrations to remain peaceful.
"Maintaining the security of Egypt is the common responsibility of everyone," presidential spokesman Ehab Fahmy told a news conference. "Dialogue is the only way to reach mutual understanding and to reach national agreement around the different issues of our homeland."