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Once undocked, Discovery did two slow laps around the space station so the crew could take photographs, before firing its engines for home.
Before leaving it took more than three hours to close all six hatches inside the two-module ISS.
They started in the Russian Zarya control module, pulling out air ducts, switching off lights and closing the doors before proceeding into Unity and repeating the routine.
Engineers on the ground helped the crew lock up by shutting off some equipment and power.
As the final hatch was sealed, astronaut Tamara Jernigan said the embryonic outpost "was a tremendously pleasant working environment".
Discovery is scheduled to return to Earth at 0600 BST on Sunday.
A small boost
Just before undocking commander Kent Rominger and pilot Rick Husband fired the shuttle's thrusters to boost the ISS nearly 10km (six miles) higher.
The new orbit will allow the connection of the next component, a Russian service module, in November.
That piece will serve as the living quarters for the station's first residents, who are scheduled to move in next March. The next temporary guests are expected in December when space shuttle Atlantis delivers more supplies.
Home sweet home
Discovery's astronauts left the outpost better equipped, cosier and quieter for those who will follow.
They unloaded 1,600 kilograms (3,600 pounds) of equipment, including tools, computers, water, clothes and even refuse bags. Most were placed in Zarya, stuffed behind panels and strapped to the walls.
"We spent a lot of this mission stowing supplies for them, so it should be pretty comfortable," said Ellen Ochoa, the astronaut in charge of the moving.
The astronauts also reduced the noise level in Zarya by placing mufflers over clattering fans, ducts and outlets, though the reduction was only about three decibels.
The first day in the ISS was taken up with repairs that successfully resurrected an Earth-ISS communication system and a solar-power storage system.
The mission began with a marathon space walk which attached cranes, tool bags and hand-rails to the outside of the ISS to aid future construction.