The collision happened on the A470, between Church Street in Rhayader and the Llangurig roundabout, shortly after 11:45 GMT on Friday.
Insp Brian Jones of Dyfed-Powys Police said two people in each car were killed.
One other person remains in hospital but the extent of their injuries is not known.
Family liaison officers are speaking with relatives of the people who died.
This crash happened just a few hours before a five-car smash on the A483 north of Welshpool.
An 83-year-old woman died at the scene of this crash.
Four people have died following a two-car crash in Powys.