OBJECTIVE Herpes viruses are characterized by their ability to establish and maintain a latent infection that can reactivate. Only 2 preliminary studies have examined herpes simplex virus (HSV) reactivation in patients receiving head and neck radiotherapy. The role of radiation therapy in the reactivation of a latent virus has not been established. The purpose of the present study was to evaluate the incidence of HSV reactivation in patients receiving radiation treatment for head and neck malignancies. METHODS Twenty patients, 19 of whom were HSV seropositive, undergoing head and neck radiation therapy were assessed weekly before and during radiation therapy, and HSV cultures were completed during cancer treatment. RESULTS Only 3.6% of the cultures were positive for HSV during radiation therapy. HSV was cultured in 4 men receiving a mean of 6,000 cGy to the head and neck area. Recovery from HSV was seen in patients nearing completion of radiation therapy. CONCLUSIONS The results of this study suggest that HSV reactivation is not common during radiation therapy. Therefore, this study does not support prophylaxis of HSV in patients undergoing head and neck irradiation.