The outing by Scott Kelly and Tim Kopra began at 7:45 am (1245 GMT), the US space agency said.
UK astronaut to take part in London marathon from space
During the three-hour spacewalk, the two men will attempt to lift the brake on the mobile transporter rail car, which carries the robotic arm from one location to another on the outside of the orbiting lab.
The brake is believed to have become stuck unexpectedly last week, and mission control in Houston has been unable to fix the problem robotically.
US astronauts step out on spacewalk
The astronauts plan to move the rail car a few inches and latch it in place, so it will not interfere with the arrival of the Russian Progress supply ship on Wednesday.
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