Questions have arisen regarding the clinical outcome and the possible selection of resistant virus when patients with genital herpes discontinue prolonged chronic acyclovir; 239 immunocompetent patients with a history of frequently recurring genital herpes who stopped successful suppressive therapy after 6 years were studied. Of the patients, 85.8% had at least one recurrence and 75% had at least two recurrences in the subsequent year (median time to first and second recurrence, 68 and 180 days, respectively). Herpes simplex virus isolates recovered from these patients had a median acyclovir sensitivity of 0.79 micrograms/mL and 4 (3.5%) were resistant (> or = 3 micrograms/mL). These values are comparable to those of pretherapy isolates and to reported values of isolates from acyclovir-naive patients. Also, paired pre- and posttherapy isolates from 13 patients showed no trend toward development of resistance. Thus, even after 6 years of acyclovir suppression, most patients continue to have recurrences, but the selection of resistant virus has not been observed.