During a placebo-controlled trial of oral acyclovir therapy for acute zoster in immunocompetent patients, we examined the blastogenic response of peripheral blood mononuclear cells and antibody titers in both placebo and acyclovir recipients to determine whether the drug affected the cell-mediated or humoral immune responses. Proliferative responses to mitogens and two dilutions of varicella-zoster virus antigen were not inhibited when fresh peripheral blood mononuclear cells were simultaneously tested in autologous sera collected before and on day 7 of a 10-day course of 2 g/day of oral acyclovir (plasma drug levels averaged 4.6 μM). Using cryopreserved cells from study days 0, 3, 7, 14, and 30, thawed and tested simultaneously, there was no significant difference at the p ≤ 0.05 level between the net proliferative responses at each time point for the two groups. On day 14, however, the proliferative response of the acyclovir group was ∼50% lower than that of the placebo group. Geometric mean antibody titer rises to varicella-zoster virus were also lower among drug recipients but not significantly so. Although this dose of acyclovir did not have a statistically significant effect on lymphocyte proliferative responses to varicella-zoster virus antigen or antibody titers, the lower values in drug recipients may be a reflection of the ability of acyclovir to terminate viral replication, thus reducing the patient's antigenic burden.