Purpose.Herpes simplex virus (HSV) can cause corneal infections in humans and lead to permanent scarring, loss of vision, and blindness. Current treatment of epithelial HSV keratitis consists of using antiviral DNA analogs. In this study, we used in vitro and in vivo models to evaluate the efficacy of six polyclonal antibodies to HSV recombinant surface glycoprotein D in treating ocular epithelial HSV.Methods.Confluent cultures of African Green monkey kidney fibroblasts (Vero cells) and normal 3-to 5-lb female New Zealand White rabbits were infected with HSV type 1, strain RE. In vitro virucidal and antiviral assays were performed, and the best of the compounds was chosen for the in vivo stage. Animals were carefully monitored until day 5 after HSV-1 inoculation, then arbitrarily divided into groups receiving, for 14 days, varying doses of: polyclonal antibodies four times a day, polyclonal antibodies three times a day, trifluorothymidine (current treatment of choice and the positive control) nine times a day, or 0.9% physiologic saline nine times a day. The animals were followed up in a masked fashion and carefully monitored for severity and resolution of the HSV infection by biomicroscopy (slit lamp) examination and viral cultures using standardized plaque assays.Results.All six of the compounds tested were effective in vitro, but one compound in particular, SP-510-50, was superior. It was used for the in vivo testing and showed antiviral efficacy in a dose-dependent manner, and at dosing four times a day, it was of comparable efficacy to trifluorothymidine (nine times a day).Conclusions.We conclude that polyclonal antibodies to glycoprotein D appear to be effective antiviral agents in vitro and in vivo in a rabbit model of HSV-1 keratitis and show promise as a new antiviral treatment for ophthalmic use.