This report evaluates the incidence of clinically significant HSV infection among 23 renal allograft recipients receiving OKT3 for treatment of steroid- or ALG-resistant acute rejection. No HSV infections occurred among the five HSV seronegative patients studied; three of 11 HSV seropositive patients (27%) treated with a ten-day course of low-dose acyclovir prophylaxis developed HSV infection. All three occurred after acyclovir was stopped. Five of six evaluable seropositive patients (83%) who did not receive acyclovir prophylaxis suffered HSV infection. We conclude that low-dose oral acyclovir may be effective in the prevention of HSV infection during OKT3 treatment of seropositive patients. Continuation of acyclovir prophylaxis for two to four weeks following the conclusion of OKT3 therapy may prevent occurrence of delayed infections.