To evaluate the effect of acyclovir (ACV) therapy on the cellular immune response, we sequentially followed 43 patients with culture-proven first episodes of genital herpes simplex virus (HSV) infection. Twenty-three patients who were treated with ACV and 20 who received placebo had blood obtained weekly during the first 6 weeks after onset of lesions and had their in vitro lymphocyte transformation (LT) response to inactivated HSV antigens measured. The mean stimulation index to HSV antigens at week 3 among patients treated with systemic ACV was 3.5 +/- 0.64 compared to 18.4 +/- 6.89 in their placebo-treated counterparts (P less than 0.05). The mean time to the development of the peak LT response to HSV antigens was 4.3 weeks in systemic-treated versus 3.4 in placebo-treated patients (P less than 0.05). The time to the development of the peak in vitro LT response to HSV antigens and the height of that response were, however, similar between topical ACV- and topical placebo-treated patients. The geometric mean HSV-2-neutralizing titer in convalescent sera was 5.4 in recipients of systemic ACV compared to 10.0 in patients treated with systemic placebo (P less than 0.05). The LT response to HSV antigen was also measured at the first recurrence in 11 patients. No differences were found in the time to first recurrence, lesion duration, number of lesions, or mean stimulation index response to inactivated HSV antigens between the six patients treated with systemic ACV during their primary episode and the five given placebo during their primary episode. Systemic ACV therapy appears to diminish the peak in vitro LT response to inactivated HSV antigens as well as to delay the time to development of that peak response. However, the cell-mediated immune response to subsequent episodes appears similar.