Herpes simplex virus commonly reactivates in seropositive transplant recipients but has not been generally thought to be transmissible by the transplanted organ itself. We studied two consecutive cases of disseminated HSV, without mucosal lesions, occurring in a heart and in a pancreatic transplant recipient, and implicate the allografts as the source of the virus. In both cases the recipients were seronegative pretransplant by complement fixation (less than 1:4), neutralization (less than 1:2), and complement enhanced neutralization (less than 1:4), and by radioimmunoprecipitation of HSV-2 antigens with serum followed by polyacrylamide gel electrophoresis (RIPA-PAGE). Both recipients' isolates were HSV-2 by restriction mapping and each donor had antibodies directed specifically against HSV-2, as determined by differential neutralization (HSV-2/HSV-1 ratios 1.46 and 1.58, where greater than 0.85 indicates antibody to HSV-2). Posttransplant, each recipient developed an antibody response with temporal antigenic specificity and complement-enhanced neutralization consistent with primary infection. These findings have important clinical and pathogenic implications and suggest that latent or reactivated HSV-2 DNA transplanted in donor tissues may cause severe infection in seronegative and immunosuppressed transplant recipients.