The supply ship brought back nearly 2,000 pounds of science experiments and old station equipment. Perhaps the most eagerly awaited cargo is nearly 500 frozen samples of blood and urine collected by station astronauts over the past year.
The Dragon is the only delivery ship capable of returning items, now that NASA's shuttles are retired to museums. Atlantis made the last shuttle haul to and from the station in July 2011.
SpaceX more formally Space Exploration Technologies Corp. launched the capsule three weeks ago from Cape Canaveral, full of groceries, clothes and other station supplies. Ice cream as well as fresh apples were especially appreciated by the station residents, now back up to a full crew of six.
It's the second Dragon to return from the orbiting lab; the first mission in May was a flight demo. This flight is the first of 12 deliveries under a $1.6 billion contract with NASA.
"It was nice while she was on board," space station commander Sunita Williams said as the Dragon backed away. "We tamed her, took her home and, literally and figuratively, there's a piece of us on that spacecraft going home to Earth."
She added to the SpaceX flight controllers in Hawthorne, Calif.: "Congratulations Hawthorne and thank you for her."
The Dragon will be retrieved from the Pacific and loaded onto a 100-foot boat that will haul it to Los Angeles. From there, it will be transported to McGregor, Texas.
The medical samples will be removed as quickly as possible, and turned over to NASA within 48 hours of splashdown, according to SpaceX. Everything else will wait for unloading in McGregor.
A Russian supply ship, meanwhile, is set to blast off this week. It burns up upon descent, however, at mission's end. So do the cargo vessels provided by Europe and Japan.
SpaceX is working to transform its Dragon cargo craft into vessels that American astronauts could fly in another four or five years. Until SpaceX or another U.S. company is able to provide rides, NASA astronauts must rely on Russian rockets to get to and from the space station.
Associated Press writer Christopher Weber in Los Angeles contributed to this story.