The resignation comes after scores were killed in a crackdown by security forces on loyalists of ousted Islamist president Mohamed Morsi.
“It has become too difficult to continue bearing responsibility for decisions I do not agree with and whose consequences I fear,” ElBaradei said.
He said his conscience was troubled over the loss of life “particularly as I believe it could have been avoided”.
“Unfortunately those who gain from what happened today are those who call for violence and terror, the extremist groups,” he said.
The health ministry said 149 people were killed in clashes across Egypt on Wednesday, prompted by a crackdown on protest camps set up by supporters of ousted president Mohamed Morsi.
It said another 1,403 people were injured as violence roiled several provinces.