The effect of trisodium phosphonoformate (PFA) has been compared to that of idoxuridine (IDU) when applied topically in both liquid and ointment preparations on herpetic keratitis in rabbits. Trisodium phosphonoformate had a therapeutic effect but was not as effective as idoxuridine in the vehicles tested. This was seen with both herpes-immunized and non-immunized rabbits. A herpesvirus mutant inducing a PFA restant DNA polymerase was used to infect rabbit corneas. A comparison of the effect of PFA on the keratitis caused by this resistant mutant and the wild type herpesvirus indicates that the therapeutic effect of PFA on the herpes keratitis was due to an inhibition of herpesvirus DNA polymerase.