The pair were Yemeni nationals and were returning from aid work in the far northern province of Saada, spokesman Adnan Hizam said by telephone.
"Two of our colleagues were shot and killed in their car ...as they were travelling back from Saada to Sanaa," Hizam said from the Yemeni capital.
A statement from the group identified the murdered employees as a field officer and a driver, adding that they believed a lone gunman was responsible but the reason for the attack remained unclear.
Saada is a bastion of support for the Iran-allied Houthi group that has been battered by Saudi-led air strikes.
A civil war in Yemen escalated in March when a coalition of Arab states led by Saudi Arabia intervened to prevent the Houthis from expanding and to reinstate the country's government from its exile in Riyadh.
"The ICRC condemns in the strongest possible terms what appears to have been the deliberate targeting of our staff," said the head of the ICRC delegation in Yemen, Antoine Grand.
Last week, the International Committee of the Red Cross said it had temporarily stopped work in the southern Yemeni port city of Aden after its office was raided by unidentified gunmen a day earlier.
The war has caused a major humanitarian crisis in the already impoverished country, which has been cut off from the outside world as air and sea ports shut down amid fighting.
With a collapse of the central government and health services throughout Yemen, aid agencies have become a critical source of food and medicine.
More than 4,500 people have been killed in the war in Yemen, which even before the latest conflict was one of the poorest in the Arab world.