The American SpaceX company's Dragon cargo capsule returns to Earth on Thursday having spent a week attached to the International Space Station.
The unmanned vehicle will fall through the atmosphere to make a splashdown in the Pacific off the California coast.
Dragon made history last Friday by becoming the first privately produced craft to visit the orbiting platform.
The mission has been a demonstration of the freight service SpaceX intends to run to the station.
It has a $1.6bn contract with the US space agency (Nasa) waiting to be triggered on the successful recovery of Dragon from the ocean.
"It's a very challenging phase of flight. Only a few countries have done this before so we're not taking this lightly," said SpaceX mission director John Coulurlis ahead of the re-entry.
Astronauts on the International Space Station (ISS) closed the hatch on Dragon on Wednesday after filling it with 660kg (1,450lb) of experiments and failed equipment that need to come back to Earth.
The crew have to unberth the cargo ship from the platform using its big robotic arm before releasing it to fly free.
Dragon must then fire its thrusters several times to take itself down and away from the station. A final burn will put it on a course for re-entry into the atmosphere.
SpaceX has organised a range of ships, planes and ground stations to track the descent of the capsule, which will be slowed in the final minutes by three big parachutes.
Dragon is projected to hit the water at 15:44 GMT (11:44 EDT; 16:44 BST).
"Our splashdown zone is about 490 nautical miles south-west of Los Angeles," explained Coulurlis.
"The recovery boats - it's a fleet of three vessels with supporting fast boats that go out to safe the spacecraft.
"It will take about two to three days to return to port. We'll then go direct to our facility in Texas for cargo unloading and further spacecraft inspection."
SpaceX - Space Exploration Technologies Corporation - has been engaged by Nasa to fulfil a logistics role at the station just as soon as it has proved its systems. The current mission was designed to see it complete a final set of performance milestones.
Nasa has another such arrangement with Orbital Sciences Corporation of Virginia, although its freighter, known as Cygnus, is still several months from making its maiden flight.
The agency hopes that by contracting out the carriage of freight it will save money which can then be re-invested in more daring activities beyond the station, at destinations such as asteroids and Mars.
The commercial cargo approach will be followed later this decade by crew transport services.
SpaceX wants this business as well, and is developing the safety and life-support equipment that would allow Dragon to double up as an astronaut taxi.
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Jonathan.Amos-INTERNET@bbc.co.uk and follow me on Twitter
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