The effect of delta-9-tetrahydrocannabinol (Delta-9-THC) on host resistance to herpes simplex virus type 2 (HSV-2) vaginal infection in the B6C3F1 mouse was determined. Animals were given Delta-9-THC or vehicle on days -1 to 2, or cyclophosphamide on day -1 or on days -1 to 2. HSV-2 was introduced intravaginally on day 0. Host resistance to virus infection was assessed by comparing frequency and severity of lesions, virus shedding and mortalities. Replicate groups of animals were bled on days 5, 8, 10, 14 and 21 post-viral inoculation to allow for screening for viraemia and for definition of the effect of Delta-9-THC on the humoral response. Animals were also employed for determination of delayed hypersensitivity responses (DHR). Virus-infected animals treated with 100 mg/kg Delta-9-THC exhibited greater severity of herpes genitalis, higher mortalities and higher mean titres of virus shed from the vagina. Suppression of the humoral response to HSV-2 occurred in animals treated with this dose of drug when compared to virus-infected vehicle controls. A delay in the onset of the DHR to HSV-2 was observed in animals receiving 100 mg/kg Delta-9-THC when compared with those receiving vehicle. These results indicate that Delta-9-THC decreases host resistance to HSV-2 vaginal infection in the B6C3F1 mouse. This decreased resistance is associated with suppression of the immune response to primary infection with HSV-2.