The first direct flight between the Israeli coastal city of Tel Aviv and Egypt's Red Sea resort of Sharm el-Sheikh took off on Sunday, Israeli national airline El-Al said.
Flight 5193, operated by El-Al subsidiary Sun d'Or, departed Ben Gurion International Airport at 0715 GMT, the carrier said in a statement.
Direct flights have long been in operation between Tel Aviv and Cairo since Egypt in 1979 became the first Arab country to sign a peace accord with Israel.
The two countries have lately bolstered their ties.
Israeli Prime Minister Naftali Bennett has twice visited Egypt after coming to power in June, and met President Abdel Fattah al-Sisi in September.
In early October, a plane branded with the logo of Egypt's national carrier Egyptair landed in Israel for the first time, a flight described as "historic" by the Israel Airport Authority.
Prior to that, Egyptian flights to Israel had been operated by an Egyptair subsidiary, Air Sinai, set up exclusively for the Israeli route and without displaying the Egyptian flag on the exterior of its planes.
Some in Egypt continue to oppose ties with the Jewish state.
The Egyptian branch of the Boycott, Divestment and Sanctions movement, which opposes Israel's occupation of Palestinian territories, has called for a boycott of two Israeli-organised dance festivals due to take place in Sinai over the coming days.
Until 2020, Egypt and Jordan were the only Arab governments to have normalized relations with Israel.
That year, they were joined by Bahrain, Morocco and the United Arab Emirates, which all now operate direct flights to the Jewish state.