Highly toxic ammonia is used to cool electronics at the orbiting outpost, and the thermal system has been plagued by problems.
Friday's outing aims to complete the final repairs to a system that broke down about three years ago.
Scott Kelly and Kjell Lindgren switched their spacesuits to battery power at 6:22 am (1122 GMT) and floated outside the orbiting outpost moments later, according to a live broadcast on NASA television.
In 2012, NASA detected a major leak in the ammonia cooling system. Astronauts replaced the ammonia pump on the station's truss in May 2013.
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After that, they will top off ammonia in the system. Should any of the liquid get on the astronauts' spacesuits, they may have to stay outside the airlock longer than planned to allow it to bake off.
Friday's spacewalk is the 190th in support of the International Space Station, which just marked 15 continuous years of human habitation.
Kelly and Lindgren did another spacewalk nine days ago to perform maintenance and upgrades outside the ISS.
He is scheduled to return to Earth in March 2016.