Lymphocyte responses to herpes simplex virus (HSV) were studied in 23 patients with recurrent herpes labialis and in 19 control subjects. Lymphocytes of seropositive, but not seronegative, controls responded to HSV by thymidine incorporation, and the supernatant fluids inhibited the migration of guinea pig macrophages. Lymphocytes from patients with a recurrent herpetic lesion responded to HSV by significantly greater thymidine incorporation than seropositive controls, but supernatants did not show an increased macrophage migration inhibition response. During the 28 days after the onset of a lesion, the thymidine incorporation to HSV fell to the level of the seropositive controls, and supernatants then induced an increased inhibition of macrophage migration. Lymphocyte responses to Candida albicans, purified protein derivative, or phytohemagglutinin did not fluctuate according to the presence of a lesion and did not differ from those of the controls. Lymphocyte responses to HSV were unaffected by culture in the presence of serum from seronegative or seropositive controls, or from patients with or without a herpetic lesion. It is suggested that in patients with recurrent herpes labialis a periodic defect of the migration inhibition response might have allowed the recurrent infection to develop, and that the increased thymidine incorporation stimulated by HSV in vitro is a result of antigenic stimulation from the lesion.