At least 72 people were killed during clashes in Cairo on Saturday, Egypt's health ministry said, after violence erupted at a demonstration in support of ousted President Mohamed Morsi.
The ministry said nine others had died in violence in Egypt's second city, Alexandria, a day earlier, putting the toll in two days of unrest at 81.
The Cairo bloodshed was the worst since Morsi's ouster in a military-led coup on July 3, prompting domestic and international condemnation, as protesters accused security forces of using live ammunition.
US secretary of state John Kerry, whose country contributes hundreds of millions of dollars in military and economic assistance to Egypt, expressed Washington's "deep concern" about the bloodshed.
In a statement, Kerry called on the authorities to "respect the right of peaceful assembly and freedom of expression".
Ahmed Aref, a spokesman for Morsi's Muslim Brotherhood, said 66 people were killed at Cairo's Rabaa al-Adawiya mosque, where supporters of the ousted president have been camped demanding his reinstatement.
An AFP correspondent counted 37 bodies in an Islamist-run field hospital at the mosque, and the emergency services said other hospitals received an additional 29 corpses.
Saturday's violence came after mass rival demonstrations in Cairo and other parts of Egypt the night before.
Witnesses told AFP that security forces had fired live bullets but the interior ministry insisted that only tear gas was used. It blamed the clashes on stone-throwing Islamists on the road to the airport.
Interior minister Mohammed Ibrahim had warned that pro-Morsi demonstrations would be dispersed "in a legal fashion" and "as soon as possible". He called on protestors to "come to their senses" and go home.
A Muslim Brotherhood statement however, said the "inhuman massacre" had only strengthened their resolve to peacefully resist the "coup d'etat".
By midday, medical workers began ferrying bodies wrapped in white shrouds to hospitals, carrying them on blood-soaked stretchers past furious Morsi loyalists.
Some wept and women ululated as each body was taken from the makeshift morgue in a marble-floored section of the mosque.
The health ministry said 748 people had been injured on Friday and Saturday, including 269 at Rabaa al-Adawiya.
The Cairo violence was the deadliest since 53 Morsi supporters were killed outside the Republican Guard headquarters in the capital on July 8.
Sheikh Ahmed al-Tayyeb, the grand imam at Al-Azhar, Egypt's top Sunni Muslim authority, condemned the violence, calling for an "urgent judicial investigation" and for those responsible to be punished "regardless of their affiliation".
Vice president Mohamed ElBaradei, who joined the transitional government that replaced Morsi's administration, denounced what he called "excessive use of force".
The National Salvation Front, a coalition of leftist and liberal groups, expressed "grief" over the deaths, but said Morsi's Brotherhood bore some of the blame for its "provocative approach".
A spokesman for European Union foreign policy chief Catherine Ashton said she deplored the killings.
Turkish prime minister Recep Tayyip Erdogan, who has infuriated Egypt's interim administration by maintaining his support for Morsi, denounced what he described as massacres.
British foreign secretary William Hague urged the authorities to "cease the use of violence against protesters, including live fire, and to hold to account those responsible".
But Egypt's interior ministry said police "did not use more than tear gas" and accused Islamists of firing on the security forces, wounding 14 policemen, two in the head.
By Saturday evening, the mood in Rabaa al-Adawiya was largely calm. Demonstrators had draped new banners with the word "peaceful" written in Arabic and English around the area.
The bloodshed came after army chief General Abdel Fattah al-Sisi, who led the coup that ousted Morsi, called for a mass show of support for a crackdown on "terrorism".
Hundreds of thousands of anti-Morsi protesters obliged, thronging Cairo's Tahrir Square and around the Ittihadiya presidential palace on Friday.
But Morsi supporters said their turnout showed many "reject the bloody, military fascist coup that wants to set the wheel of history back".
On Friday, authorities remanded Morsi in custody for 15 days, accusing him of the "premeditated murder of some prisoners, officers and soldiers" when he broke out of prison during the 2011 uprising that toppled veteran strongman Hosni Mubarak, state news agency MENA said.
He also stands accused of conspiring to "storm prisons and destroy them... allowing prisoners to escape, including himself".
Egypt, the Arab world's most populous country, has been rocked by violence that has now killed more than 300 people in the less than four weeks since the coup.
Political polarisation has raised fears of prolonged violence, and even a militant backlash, including in the Sinai Peninsula, where the army is already facing daily attacks.
A civilian was killed and a police officer died of his injuries there, security sources said.