• A herpes simplex stromal keratitis rabbit model, which was produced by intrastromal injection of live virus, was used to evaluate the effects of local antivirals on the natural course of the disease. Topical trifluridine (trifluorothymidine) and vidarabine monophosphate (adenine arabinoside monophosphate), when given early and frequently, suppressed the disease, indicating that viral replication was important in initiating the disease. However, seven days after the stromal disease had begun to develop, neither drug had an appreciable effect. Since the early drug effect had suggested adequate drug penetration, the absence of drug effect later in the disease indicates that viral multiplication may not be important in maintaining the disease. Immunologic reactions may control the disease once the cornea is antigenically altered by the initial infection. Subconjunctivally injected trifluridine was not effective.