Five people died as protesters flooded Egypt's streets calling for Islamist President Mohamed Morsi to step down, in massive demonstrations reminiscent of the 2011 revolt which ultimately paved the way to his leadership.
"It is the biggest protest in Egypt's history," a military source told AFP on condition of anonymity, adding that "millions" of people were on the streets across the country.
But as clashes broke out later on Sunday, five people were killed.
A 26-year-old man died and several others were wounded as protesters attacked the Cairo headquarters of the Muslim Brotherhood, a hospital official said.
Television pictures showed the building on fire as dozens of people attacked it, throwing stones and fire bombs.
Supporters of the Brotherhood fired buckshot at the attackers in a bid to repel them, an AFP journalist at the scene witnessed. Later, automatic weapons fire could be heard around the building.
Gehad al-Haddad, a spokesman for the Islamist movement, said around 150 "unidentified thugs" had attacked the offices.
Three people were killed in the central province of Assiut when gunmen on a motorbike opened fire on protesters, a security official said.
One person died and 40 others were injured when supporters and opponents of Morsi clashed in Beni Sueif province, south of Cairo.
Both those incidents took place outside offices of the Freedom and Justice Party, the political arm of the Muslim Brotherhood.
"Dialogue is the only way through which we can reach an understanding...," Morsi's spokesman Ehab Fahmy told reporters.
"The presidency is open to a real and serious national dialogue."
But as chants of "Leave!" rang out around Cairo, the main opposition National Salvation Front called for a campaign of peaceful civil disobedience.
They urged Egyptians to stay on the streets until Morsi stepped down.
One opposition leader called on the army to intervene if Morsi refused to quit.
"The armed forces must act, because they have always been on the side of the people," which "has expressed its will", said Hamdeen Sabahi, who came third in the 2012 presidential election.
The best outcome would be if Morsi went of his own accord, he added.
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Anti-Morsi protests were held in the coastal city of Alexandria, the Nile Delta cities of Mansura, Menuf, Tanta and Mahalla, the canal cities of Suez and Port Said and in the president's hometown of Zagazig.
In Cairo's Tahrir Square, protesters waved red cards and Egyptian flags as patriotic songs boomed from large speakers.
"The people want the ouster of the regime," the protesters chanted, echoing the signature slogan of the 2011 revolt that ousted Hosni Mubarak and brought Morsi to power.
Morsi supporters have been holding counter rallies for days to defend his legitimacy and there had been fears of major confrontations.
But Sunday's anti-government protests eclipsed their gathering in Cairo's Nasr City neighbourhood, which the army estimated to number around 25,000 people.
Police and troops were deployed at key buildings nationwide, including the vital Suez Canal waterway, security officials said. Hospitals were put on high alert.
Banks and most offices closed on Sunday, a working day in Egypt.
The grassroots movement Tamarod -- Arabic for rebellion -- said it had more than 22 million signatures for a petition demanding Morsi's resignation and fresh elections.
The figure could not be verified.
Morsi won last year's election by 13.2 million votes to 12.3 million.
Last week, eight people including an American were killed and scores more injured as rival demonstrators clashed.
Morsi, previously a senior Brotherhood leader, is Egypt's first freely elected president, catapulted to power by the uprising that ended three decades of Mubarak rule.
His opponents accuse him of betraying the revolution by concentrating power in Islamist hands and of sending the economy into freefall.
Morsi supporters say he inherited many problems from a corrupt regime, and that he should be allowed to complete his term which ends in 2016.
Any attempt to remove him from office is a coup against democracy, his supporters say.
Opponents insist calls for his resignation are aimed at restoring the revolution's cornerstones of democracy, freedom and social justice.
"We will not allow a coup against the president," senior Brotherhood leader Mohamed al-Beltagui said.
The army, which led a tumultuous transition after Mubarak's ouster, has warned that it will intervene if there is major unrest.
Since taking office, Morsi has battled with the judiciary, the media and the police. The economy has nosedived, investment has dried up, inflation has soared and the vital tourism sector has been battered.
In a televised speech on Wednesday, Morsi warned that polarisation threatened to "paralyse" Egypt and tried to placate protesters with appeals for dialogue and promises of constitutional reform.