Aid agencies have been trying to reach millions of people in Yemen, who lack basic supplies because of the conflict that has been raging there for months.
The killings come just over a week after gunmen raided the ICRC`s offices in the southern port city of Aden.
They held staff at gunpoint and demanded money, vehicles and other equipment.
The attack, one of at least 10 recent security breaches the ICRC has faced in Aden, prompted the organisation to temporarily suspend its local aid operations.
`Brutal targeting`
ICRC spokeswoman Sitara Jabeen told the BBC that the aid workers - both Yemeni - were driving from Saada province to Sanaa with two colleagues in two vehicles when gunmen stopped them and then opened fire.
One of the workers was killed instantly, while the other was rushed to a nearby hospital where he succumbed to his injuries, she added.
Their two colleagues were unharmed in the attack.
The ICRC`s delegation in Yemen wrote on Twitter that it was "shocked and appalled" by the incident.
"We condemn in strongest possible terms the brutal targeting of the staff who put themselves in harm`s way to help improve lives of others," it added.
Ms Jabeen said the Red Cross would halt all movement by its staff as a precaution.
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