The collision, involving a silver Peugeot 307 and a silver Hyundai i10, happened on the A4046 near Cwm, Ebbw Vale, at about 22:20 BST on Friday.
The driver of the Peugeot died at the scene.
His front seat passenger and the driver of the Hyundai are being treated at the University Hospital of Wales, Cardiff.
Gwent Police are appealing for witnesses.
A 41-year-old man died and two other people suffered serious injuries when the cars they were travelling in crashed in Blaenau Gwent.