Commander Barry "Butch" Wilmore and flight engineer Terry Virts emerged from the station airlock after placing their suits on internal battery power at 6:51 am (12:51 GMT), NASA said.
The team's goal for the six-plus hour spacewalk is to route two bundles of cable, lubricate parts of the space station's robotic arm and prepare for another operation later this year to move modules around at the orbiting outpost.
The work aims to set up additional docking ports -- which are essentially parking spots for space taxis -- at the ISS for the arrival of more crew-carrying spacecraft.