The plane left Paris at 11.09pm on Wednesday night (21.09 GMT).
The airline said contact was lost around 16km/10 miles inside Egyptian airspace at 2.30am local time (00.30 GMT).
Among the passengers were 30 Egyptians, 15 French, two Iraqis, and one each from the UK, Belgium, Kuwait, Saudi Arabia, Sudan, Chad, Portugal, Algeria and Canada.
EgyptAir says the plane’s emergency devices – possibly an emergency locator transmitter or beacon – sent a signal that was received at 4.26am local time, two hours after the last radar contact.
Search and rescue efforts are underway at the site where contact was lost, around 280km (175 miles) north of Egypt’s coast. Greece has joined the search and operation, and France has pledged boats and planes to assist.
The plane, on its fifth journey of the day, was travelling at 37,000 feet when it disappeared from radar.
EgyptAir says the captain has 6,275 flying hours, including 2,101 on the A320; the copilot has 2,766. The plane was manufactured in 2003.
In March, an Egypt Air Flight MS181 was hijacked by one Seif Eldin Mustafa who has claimed to be wearing a suicide explosive belt.
The aircraft, an Airbus A320, also carrying 56 passengers from Alexandria to Cairo, along with six crew and a security official was forced to divert to Larnaca airport in Cyprus.