Frenchman Thomas Pesquet and three other astronauts leave the International Space Station on Monday, and are due to land off Florida after spending more than six months in space.
The trip should last almost 18 hours.
The crew of Crew-2, composed of Thomas Pesquet, the Japanese Akihiko Hoshide and the Americans Shane Kimbrough and Megan McArthur, return to Earth before the arrival on board the ISS of the four astronauts of Crew-3, whose take-off has been delayed several times mainly because of the weather.
VIDEO.
Follow the departure of Thomas Pesquet from the ISS live.
"As we prepare to leave, there is a bit of a bittersweet feeling," Thomas Pesquet commented early Friday at a press conference from the space station.
“We might never come back to see the ISS again, and it truly is a magical place.
The 43-year-old French astronaut is completing the second mission of his career in orbit, "Alpha".
He arrived aboard the ISS with his teammates on April 24.
To read also Thomas Pesquet back on Earth Monday: "He will be a future great ambassador of the planet"
After its vertiginous descent, the Dragon capsule will be recovered from one of the possible arrival points, off Florida, by a SpaceX boat.
Crew-2 is the second regular mission carried out by Elon Musk's company on behalf of NASA.
The takeoff of the third is finally scheduled for Wednesday at 9:03 pm Florida time (2:03 GMT Thursday), aboard a Falcon 9 rocket from Cape Canaveral.
Crew-3 astronauts Americans Raja Chari, Kayla Barron and Tom Marshburn, as well as German Matthias Maurer, have been in quarantine at the Kennedy Space Center for days.