The neural spread of herpes simplex virus (HSV) via sensory nerves is an essential component of disease pathogenesis. Capsaicin, a specific toxin for sensory C-type fibers, interferes with neuronal function including axonal transport. Capsaicin treatment of guinea pigs before intravaginal HSV inoculation did not prevent ganglionic infection but ameliorated cutaneous herpetic disease, suggesting that anterograde but not retrograde virus spread involved a capsaicin-sensitive process. Similarly, treatment of latently infected animals reduced both spontaneous and ultraviolet radiation-induced herpetic recurrences, suggesting that capsaicin interfered with the anterograde spread of reactivated virus. These results suggest that the centrifugal spread of virus may involve either different pathways or mechanisms than are involved in centripetal HSV spread. The use of selective neuropharmacologic agents such as capsaicin may prove useful in further defining the pathophysiology of HSV disease.