The spacewalk by France's Thomas Pesquet, 39, and American Shane Kimbrough, 49, officially began at 7:24 am (1124 GMT) when the duo switched their spacesuits to internal battery power.
Pesquet and Kimbrough will work separately for most of the six-and-a-half hour spacewalk as they prepare to install new docking ports for the next generation of commercial spacecraft and do some minor space station repairs and maintenance.
The new crew spaceships, being designed by SpaceX and Boeing, should begin flying astronauts to the station in the coming years, as early as 2018.
Currently, the only way the world's astronauts can reach orbit is by buying a ride aboard Russia's Soyuz capsules, at $81 million per seat.
Friday's spacewalk is the second of Pesquet's career, and the fifth for Kimbrough.
"Going outside is always a gee-whiz moment for me," Kimbrough said in an interview on NASA television this week, adding that it was also "really satisfying" to see Pesquet perform so well on his first spacewalk back in January.
On Thursday, Pesquet wrote on Twitter: "Feeling prepared for my second spacewalk tomorrow!"
Pesquet is the fourth Frenchman to ever walk in space, and the 11th European.
Friday's goal is to prepare for the installation of the second of two parking spots for space taxis, known as the International Docking Adapter.
The spacewalkers "will disconnect cables and electrical connections on the pressurized mating adapter (PMA-3) to prepare for its robotic move Thursday, March 30" during another spacewalk, NASA said in a statement.
The mating adapter equipment "will be moved from the port side of the Tranquility module to the space-facing side of the Harmony module."
In its new location, it will become the home for the International Docking Adapter, to be delivered on a future flight of a SpaceX Dragon cargo ship.
Pesquet and Kimbrough also plan to install new computer equipment outside the space station, and will lubricate and inspect the space station's robotic arm, used to grab approaching spacecraft and move items outside the global laboratory.
Other tasks include inspecting a radiator valve suspected of a small ammonia leak and replacing cameras on the Japanese segment of the outpost, the US space agency said.
The next outing on March 30 will include Kimbrough and American astronaut Peggy Whitson, making the eighth spacewalk of her career.
A third spacewalk on April 6 is to include Pesquet and Whitson, who will surpass the record for spacewalks by any female astronauts.
Later in April, the 57-year-old Whitson will also break the record for most number of days spent in space by an American astronaut.
The current US record of 534 days is held by astronaut Jeff Williams.
Russian cosmonaut Gennady Padalka holds the record for the most cumulative days ever in space, at 879 days over five career trips.
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