Some reports say a bomb was lobbed into a chapel adjacent to one of the cathedral’s walls in the centre of the city but others said it was planted inside.
The spiritual leader of Egypt’s Orthodox christian community, Pope Tawadros II has his office in St Mark’s Cathedral.
State television reported that a security official said a bomb made of TNT appeared to have been the cause of the explosion.
Ambulances lined up outside the church in the capital’s Abbasiya district to evacuate the dead and wounded.
A crowd gathered outside the church chanting: “Tell the sheikh, tell the priest, Egyptians’ blood is not cheap”.
The deadly attack is the second to hit Cairo in two days.
There was no claim of responsibility for the attack, but jihadists in Sinai have targeted Christians before, as well as Muslims they accuse of working with the government.
Six policemen were killed on Friday in a bomb attack claimed by a group suspected by authorities of having links to the outlawed Muslim Brotherhood.