Oral acyclovir was found to be safe and effective for the prevention of herpes simplex virus reactivation after marrow transplantation in a double-blind, placebo-controlled trial. Acyclovir or placebo was administered to 49 patients for 5 weeks beginning 1 week before transplantation: 5 of 24 patients receiving acyclovir developed herpes simplex virus infection during prophylaxis, compared to 17 of 25 patients receiving placebo (p less than 0.01). The median time to first virus reactivation was significantly longer among patients receiving acyclovir (78 days versus 9 days after transplant, p = 0.006). The effect was even more pronounced when the analysis was adjusted for drug compliance: Among patients taking a minimum of 40% of their prescribed drug, acyclovir was 96% virologically effective and 100% clinically effective during the period of administration. Acyclovir use was also associated with significantly more rapid marrow engraftment in patients receiving methotrexate. No virus resistant to acyclovir was isolated. Oral acyclovir provides effective prophylaxis against reactivation of herpes simplex virus among severely immunosuppressed patients able to take orally administered drugs.