The combined antiviral effects of acyclovir (ACV) and ribavirin (Rbv) on herpes simplex virus type 1 (HSV-1) and pseudorabies virus (PRV) in cell cultures and on experimental HSV-1 keratitis in rabbits were studied. The antiviral activity in vitro was based on cytopathogenicity inhibition and yield reduction. The combination of the two drugs exhibited synergy as evaluated graphically (isobolograms). Rbv also potentiated the antiviral effect of ACV in vivo, in the experimental HSV-1 keratitis model in rabbits. This was evident from both the severity of corneal lesions and virus shedding in the tear film. The potentiating effect of Rbv on the anti-HSV-1 activity of ACV in vitro was reversed by guanosine.