ISS commander, Russia's Maxim Surayev, his American colleague Reid Wiseman and German Alexander Gerst from the European Space Agency have been onboard the space laboratory for 165 days.
The crew undocked from ISS at 0031 GMT today and are expected to reach Earth's surface by 10-58 pm, touching down northeast of Arkalyk, Kazakhstan, NASA said.
The three men were pictured smiling and with their arms around each other before hitching the ride back home.
The US space agency said the "departure of Wiseman, Gerst and Surayev marks the end of Expedition 41," referring to their mission to the ISS to carry out equipment repairs, maintenance and experiments.
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Another three-person crew remains aboard the ISS to "continue research and maintenance aboard the station," NASA said.
NASA Television is airing live coverage of the Soyuz deorbit burn and landing at https://bsmedia.business-standard.comwww.Nasa.Gov/nasatv.
NASA lost its ability to reach the space station when the shuttle program ended in 2011 after 30 years.
The US space agency has helped fund private companies in a push to restore US access to the ISS.
In the meantime, the world's astronauts must rely on Russia's Soyuz spacecraft to get to the ISS and back, at a cost of USD 70 million per seat.