Herpes simplex genitalis is an increasingly common primary or recurrent HSV infection. Acyclovir (ACV) has been found to diminish virus shedding and clinical symptoms in patients with first episode genital HSV when given topically or intravenously. As most patients with first episode disease do not require hospitalization and recurrent disease is usually less severe than the primary infection, out-patient treatment forms the basis of practical management. Acyclovir is absorbed orally with plasma concentrations which exceed in vitro inhibitory concentrations for HSV1 and HSV2. In double blind studies in over 100 recipients with first episode HSV, oral ACV treatment (200 mg, 5 times daily) significantly reduced virus shedding, new lesion formation, duration of genital lesions and clinical symptoms in both men and women when compared with placebo recipients. No toxicity was observed. Recurrence rates following the first episode were similar in placebo and ACV groups. A multi-centre double blind trial of oral ACV treatment of recurrent HSV infection in 250 patients showed that the duration of virus shedding and lesions was significantly shorter in ACV versus placebo recipients. These effects were more pronounced when therapy was self-initiated by patients early on during a recurrence or during the prodromal period. Oral acyclovir has significant clinical and virological effects in both primary and recurrent genital HSV infections.