Topical diclofenac sodium is a non-steroidal anti-inflammatory drug that is being developed for use in the control of postoperative and medical inflammation. A comparison was made of 0.1% diclofenac with 1% prednisolone sodium phosphate, 0.03% flurbiprofen, and a vehicle placebo in rabbit eyes with acute herpetic keratitis in a double-masked study. Maximum corneal epithelial involvement was observed in each group on day 6 postinoculation, and in eyes subsequently treated with prednisolone, the corneal epithelial involvement appeared to be more severe and to resolve more slowly. Conjunctivitis and corneal clouding peaked on days 6 to 7 for all treatment groups and remained most severe in the placebo-treated eyes, followed closely by those treated with prednisolone. The duration of virus shedding was the same for placebo-, flurbiprofen-, and diclofenac-treated groups (50% or more were virus negative by day 10 or 11). Only prednisolone-treated eyes had an extended period of virus shedding, and the rabbit mortality rate in this group was slightly higher. It thus appears that topical diclofenac does not exacerbate acute herpes keratitis; diclofenac-treated eyes displayed less or at least no more severe disease than did the eyes treated with the other anti-inflammatory agents tested, and shedding of virus into tears was not prolonged.