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Atlantis commander Chris Ferguson bids farewell to the ISS
When the orbiter reaches Earth on Thursday morning, it will bring to a close Nasa's 30-year re-usable spaceplane programme.
The shuttle pushed away from the station on schedule at 0628 GMT.
"Farewell ISS, make us proud," said Atlantis commander Chris Ferguson as his ship slipped away.
The shuttle moved to a point about 200m (600ft) off the bow of the platform, which then swung about 90 degrees using thrusters on its Russian stern.
The manoeuvre enabled Atlantis to fly over the 400-tonne structure, to take photographs along its truss, or backbone, and of the ends of some of the modules.
This imagery will help engineers on the ground to understand better how the various elements that make up the ISS are coping in the harsh environment of space.
Atlantis' crew of four had presented the station crew of six with two leaving presents before climbing aboard the orbiter and closing the hatch.
One was a model of the shuttle - a reminder of the pivotal role the vehicle has played in building the station. The other was a small American flag flown on the very first space shuttle mission in 1981. This flag will be handed to the first American astronauts to reach the ISS on one of the privately operated space vehicles Nasa is now encouraging to replace the shuttle.
Imagery acquired from Atlantis will be used to assess the ISS structure
Undocking was sounded - as tradition would have it - by a bell being rung out on the station, and then speeches from Ferguson and Ron Garan, the lead Nasa resident on the outpost.
"Atlantis departing the International Space Station for the last time," Garan called out. "Thank you for your 12 docked missions to the ISS, and for capping off 37 space shuttle missions to construct this incredible orbiting research facility."
Ferguson replied: "As the ISS now enters the era of utilisation, we'll never forget the role played by the space shuttle in its creation. Like a proud parent, we anticipate great things to follow from the men and women who build, operate and live there."
Atlantis is set to touch down on Kennedy's runway at 0557 local time (0957 GMT) on Thursday.
It is carrying about 2.5 tonnes of unneeded materials and rubbish from the ISS.
Nasa's orbiter programme officially ends 30 days after wheel stop, although it will take about two years to close all activities, including the archiving of decades of engineering data.
Atlantis itself will be made safe for public display at the Kennedy visitors complex.
Shuttle retirement will leave a gap in America's astronaut-launch capability that is unlikely to be filled for at least three or four years.
In the short-term, the US will have to rely on Russian Soyuz rockets and capsules to get its men and women to and from the ISS.
Sometime mid-decade, the first of a range of commercial American launch vehicles should be ready to fly.
On Monday, Nasa signed an agreement with the Colorado-based United Launch Alliance company to assess its Atlas 5 rocket for crew operations. The review will help determine whether the Atlas is fundamentally safe enough to lift humans into orbit.
BBC News
