Barack Obama departed late Tuesday en route to Israel for a four-day trip to the Middle East, a journalist traveling with the US president said.
The president's airplane, Air Force One, took off at 8:15 pm (0015 GMT Wednesday) from Andrews Air Force Base outside the US capital.
Obama is scheduled to touch down in Tel Aviv at around 1030 GMT, according to the president's official schedule.
US officials have styled Obama's trip as an effort to reconnect with Israeli Prime Minister Benjamin Netanyahu, with whom he had a delicate relationship during his first term, and to coordinate on key issues like Iran and Syria.
Obama will also travel to see Palestinian leaders on the West Bank and visit Jordan on the first foreign policy mission of his second term.
Administration officials have signaled there will be no major peace initiative during the trip, with Obama stating he is traveling to the region to "listen" to both sides.
Obama will meet Netanyahu in Jerusalem, and Palestinian president Mahmud Abbas and his premier Salam Fayyad in Ramallah, to hear their perspective on how to resolve the decades-long conflict.
"My goal on this trip is to listen. I intend to meet with Bibi (Netanyahu) ... I intend to meet with Fayyad and Abu Mazen (Abbas) and to hear from them what is their strategy, what is their vision, where do they think this should go?" Obama told Israeli television.