Fifty people, mostly children, were killed when a train slammed into a school bus as it crossed tracks in a city south of Cairo.
All but two of the dead were children, aged around four to eight, a senior security official in Assiut, near the site said.
One woman and the bus driver also died, he added.
The bus was broken in half by the force of the crash. Blood was spattered on the front of the engine and school bags and text books, some bloodstained, were strewn around.
Witnesses said barriers at the rail crossing were open when the train hit the bus.
Transport Minister Mohamed Rashad and the head of the railways authority resigned, and President Mohamed Mursi said those responsible would be held to account.
Egypt's roads and railways have a poor safety record and Egyptians have long complained that successive governments have failed to enforce even basic safeguards, leading to a string of deadly crashes.
State media reported that as well as 50 dead, 15 or more people were injured. A medical source said as many as 28 were injured, 27 of them children.
President Mursi ordered his ministers to offer support to the families of those killed, the official news agency said.
Prime Minister Hisham Kandil ordered investigations into anyone responsible for the crash and travelled to the scene.
Victims' families protested at the crash site, the state news agency reported. Officials sought to reassure them the case would be investigated and they would receive help, it said.
Earlier this month, at least three Egyptians were killed and more than 30 injured in a train crash in Fayoum, another city south of Cairo.
In July, 15 people were injured in Giza, close to the capital, when a train derailed.
Egypt's worst train disaster was in 2002 when a fire ripped through seven carriages of an overcrowded passenger train, killing at least 360 people.