The official says career diplomats Omar Amer and Ihab Fahmy have stepped down after nearly five months speaking on behalf of Morsi.
The move compounds the woes for Morsi as he faces massive protests calling for him to step down.
Six Cabinet ministers quit yesterday and the military gave the president a 48-hour ultimatum to work out his differences with the opposition or it will intervene.
The ultimatum expires early tomorrow.
Islamist President Mohamed Morsi snubbed an army ultimatum threatening to intervene if he did not meet the demands of the people.
The opposition too expressed concern that the military was poised to play a political role in the deeply divided country, even as the army hastened to damp down talk of an imminent "coup".
An army statement, read out on television Monday, had given Morsi 48 hours to comply with its call, after millions of people took to the streets nationwide to demand the Islamist leader step down.
"If the demands of the people are not met in this period... (the armed forces) will announce a future roadmap and measures to oversee its implementation," it said.
In a statement issued overnight, the presidency insisted it would continue on its own path towards national reconciliation.
The army declaration had not been cleared by the presidency and could cause confusion, it said.
The presidency also denounced any declaration that would "deepen division" and "threaten the social peace".
The president was consulting "with all national forces to secure the path of democratic change and the protection of the popular will", it added.
Morsi's supporters, who have also taken to the streets to defend his legitimacy, say any attempt to remove the democratically elected president from power is no less than a coup.
Egypt's main opposition coalition said Tuesday it would not support a "military coup" and trusted that the army statement giving political leaders 48 hours to resolve the current crisis did not mean it would assume a political role.
"We do not support a military coup," the National Salvation Front (NSF) said in a statement. "We trust the army's declaration, reflected in their statement (Monday), that they don't want to get involved in politics, or play a political role," it said.
The army quickly issued a denial there was any attempt at a "coup", saying that army chief Abdel Fattah al-Sisi's statement was merely aimed at "pushing all political sides to quickly find a solution to the current crisis."
As the country's political uncertainty grew, Morsi was hit with a spate of resignations, including by his foreign minister Mohammed Kamel Amr and the ministers of tourism, environment, investment and legal affairs.
Presidential spokesman Ehab Fahmy and cabinet spokesman Alaa al-Hadidi also resigned, officials and the media reported.
Adding to Morsi's woes, an Egyptian court on Tuesday ordered the reinstatement of Abdel Meguid Mahmud, the public prosecutor he had sacked in November.
US President Barack Obama, whose government is a major military aid donor to Egypt, called Morsi to warn him that the voices of all Egyptians must be heard, a White House official said Tuesday.
Obama placed the call from Tanzania, on the final stop of his African tour and told him Washington was committed to "the democratic process in Egypt and does not support any single party or group," the official said.
The increasingly-isolated Morsi is Egypt's first freely elected president.
A longtime leader of the powerful Muslim Brotherhood, he was catapulted to power by the 2011 uprising that ended three decades of dictator Hosni Mubarak's rule.
Monday's army statement came just a day after millions of protesters took to the streets across Egypt, calling for Morsi to step down.
It received a rapturous welcome from Morsi's opponents who spilled into the streets in Cairo, Alexandria and several other provinces, waving flags, chanting for the army and against Morsi.
Tamarod, the grassroots campaign behind Sunday's massive protests against Morsi, also hailed the statement by the armed forces which it said had "sided with the people".
It "will mean early presidential elections", Tamarod's spokesman Mahmud Badr told reporters.
Egypt has been deeply divided between Morsi's Islamist supporters and a broad-based opposition.
Tamarod had issued its own ultimatum, giving Morsi until 5:00 pm (1500 GMT) on Tuesday to quit or face an open-ended campaign of civil disobedience.
Sixteen people died in protests on Sunday, including eight in clashes between supporters and opponents of the president outside the Cairo headquarters of the Muslim Brotherhood, to which Morsi belongs, the health ministry said.
Early on Monday, protesters set the Brotherhood's headquarters ablaze before looting it.
Morsi's opponents accuse him of having betrayed the revolution by concentrating power in Islamist hands and of sending the economy into freefall.
His supporters say he inherited many problems from a corrupt regime, and that he should be allowed to complete his term, which ends in 2016.
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