The intraneuronal transport of herpes simplex virus (HSV) is an essential component in disease pathogenesis. Capsaicin, a neuropharmacologic agent lacking direct antiviral activity, has been shown to protect animals against HSV-induced disease. It has been hypothesized that capsaicin acts by interfering with the intraneuronal transport of virus. Since animal models have been useful in studying the spread of virus, we used two guinea pig models of zosteriform herpes to examine the effect of capsaicin on HSV spread. Capsaicin was subcutaneously administered to Hartley guinea pigs prior to intravaginal or cutaneous HSV-2 inoculation. Treatment did not prevent the development of herpetic vesicles at the site of inoculation but significantly reduced the zosteriform spread of lesions in male and female animals. Further, after recovery from primary infection, capsaicin-treated male guinea pigs were observed to have fewer days with recurrent herpetic lesions. These results suggest that capsaicin-sensitive nerve fibers play a role in the pathogenesis of primary and recurrent HSV infections. Capsaicin appears to reduce the severity of cutaneous HSV infections by interfering with the spread of virus.