AIMS: Possible risk factors were evaluated for herpes simplex virus (HSV) epithelial keratitis in patients with stromal keratouveitis. METHODS: The study population included 260 patients who had active stromal keratitis and/or iridocyclitis without epithelial disease and who were enrolled in one of three clinical trials of the Herpetic Eye Disease Study. Study treatment involved a 10 week course of topical placebo, topical prednisolone phosphate, or topical prednisolone phosphate with oral acyclovir. All groups received topical trifluridine four times daily for 3 weeks then twice daily for another 7 weeks. Patients were examined for HSV epithelial keratitis for 16 weeks. RESULTS: Dendritic or geographic epithelial keratitis occurred in 12 (4.6%) study patients. Adverse effects attributable to trifluridine prophylaxis were acute allergic blepharoconjunctivitis in 10 (3.8%) study patients and corneal epithelial erosions in 11 (4.2%) study patients. No significant difference in the occurrence of HSV epithelial keratitis was found among the study treatment groups: one (2.0%) of 49 topical placebo treated patients, nine (6.5%) of 138 patients treated with topical corticosteroids without acyclovir, and two (2.7%) of 73 patients treated with topical corticosteroids and oral acyclovir. Univariate exponential models suggested that patients with a history of previous HSV epithelial keratitis and non-white patients were more likely to develop HSV epithelial keratitis during treatment of stromal keratouveitis. CONCLUSION: Individuals with prior HSV epithelial keratitis and certain ethnic groups may have a higher rate of recurrent epithelial keratitis during the acute treatment of HSV stromal keratouveitis.