During the spacewalk, expected to last six and a half hours, flight engineers Tom Marshburn and Chris Cassidy will inspect and possibly repair the ammonia leak that affected the US segment of the orbiting laboratory on Thursday.
"Spacewalk under way to repair ammonia leak," said the headline of a US space agency statement. Ammonia is used to cool the station's power system.
However the astronauts did not detect any signs of ammonia leaking into space in the first hour of their mission, NASA television said, adding that they "have reported nothing out of the ordinary so far."
It will be the 168th excursion in support of the orbiting laboratory and the fourth for both Marshburn and Cassidy, who have worked together before.
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ISS commander Chris Hadfield and Russian cosmonaut Pavel Vinogradov helped Marshburn and Cassidy suit up for the excursion, inspecting their gear and harnesses and making a series of elaborate checks.
"Good Morning, Earth! A complex & vital day on Space Station," Hadfield tweeted before the spacewalk began.
"Busy day!"
NASA has stressed that the lives of the multinational crew were not in danger, but both Russian and US space experts called the leak "serious".
"After each such sorties guys come back like they've been through a good battle, with bruised hands and grazed shoulders," Vladimir Solovyov, flight director for the Russian segment of the space station, was quoted as saying.
Norm Knight, NASA chief flight director, said earlier that the spacewalk would be "precedent-setting" at the space station because it had to be performed on short notice, adding that it was "probably one of the fastest ones" that the US space agency has had to assemble.
NASA said ammonia was leaking from the same general area as in a previous episode in November last year.
A meteorite or a piece of orbital debris is suspected to have hit the cooling radiator and caused the problem, which International Space Station program manager Michael Suffredini described as an "annoyance because of all the work we have to do to work around the problem.