Previously, we demonstrated that HPMPC, a new, broad-spectrum antiviral agent, inhibited adenovirus type 5 in the New Zealand (NZ) rabbit ocular model (Cornea 1992; 11:529–33). Historically, no antiviral agent has been demonstrated to be effective against both herpes simplex virus type 1 (HSV-1) and adenovirus eye infections in an experimental animal model. In this study, we compared topical 0.2% HPMPC to 1% trifluridine and vehicle control in the NZ rabbit HSV-1 keratitis model. Using a double-masked, two-eye design, NZ rabbits were inoculated in both eyes with HSV-1 W strain (105pfu/eye), and dendritic keratitis and HSV-1 ocular titers were measured serially. Compared with the control group, both topical 0.2% HPMPC and 1% trifluridine significantly reduced healing time of HSV-1 dendritic keratitis, lowered HSV-1 ocular titers on days 3 through 11, and shortened duration of HSV-1 shedding in the tear film. For all outcome parameters measured, topical 0.2% HPMPC was as effective as 1% trifluridine. A new concept of a broad-spectrum topical antiviral agent was shown to be effective against HSV-1 in an NZ rabbit keratitis model, and further development toward clinical application appears desirable.