Neuropharmacologic agents able to disrupt normal virus-neuron interactions may provide an alternative strategy for the treatment of herpes simplex virus (HSV) infections. We have previously shown that prophylactic treatment with capsaicin, a natural compound that alters function in sensory neurons, can protect guinea pigs against cutaneous HSV disease, even though the compound has no direct antiviral activity. Here we have examined the ability of civamide, the cis isomer of capsaicin, to interfere with HSV disease. We show that, even when the onset of treatment was delayed until after intravaginal virus challenge, primary genital skin disease severity was significantly reduced. In addition, animals treated during primary infection subsequently experienced a long-lasting reduction in recurrent disease. Civamide treatment during latent infection also significantly reduced recurrent disease, although for a shorter period. Further a single weekly treatment with civamide during latent infection was sufficient to reduce recurrent disease, indicating that an infrequent suppressive maintenance therapy might be possible.