Corneal graft survival in 13 patients (14 eyes) receiving oral acyclovir after penetrating keratoplasty for herpes simplex keratitis was compared with that in nine patients (nine eyes) who underwent penetrating keratoplasty for herpes simplex keratitis without postoperative acyclovir. Mean age, duration of disease, and time of follow-up did not differ in the two groups. There were no recurrences of herpes simplex keratitis in any patient receiving acyclovir during a mean follow-up of 16.5 months compared with a 44% (four of nine) recurrence rate in patients without acyclovir during a mean follow-up of 20.6 months (p < 0.01). Graft failure occurred in 14% (2 of 14) of acyclovir treatment eyes compared with 56% (five of nine) without acyclovir. Long-term prophylactic oral acyclovir significantly decreased the recurrence of herpes simplex keratitis and reduced corneal graft failure in patients who had a history of recurrent herpes simplex keratitis and who had undergone penetrating keratoplasty.