Patient-initiated treatment of recurrent genital herpes with topical acyclovir was compared with placebo treatment in a multicenter collaborative trial involving 309 patients. No differences were found between the group using acyclovir and that using placebo except that herpes simplex virus was excreted for a shorter period by women using acyclovir. This difference was partially accounted for by the fact that some patients whose viral culture results subsequently proved positive began to use their medication before lesions formed. One hundred patients initially applied ointment within 6 hr of onset of the prodrome and before actual lesion formation. Separate analysis of this group showed a diminished duration of viral excretion by women using acyclovir and a reduced interval between lesion formation and total crusting in men using acyclovir, but both differences were of only borderline significance (.05 less than P less than .10). The results indicate that patient-initiated therapy with topical acyclovir in polyethylene glycol exerts no clinically significant effect on recurrent genital herpes.