Antigen-stimulated lymphocyte transformation, as measured by 3H-thymidine incorporation, and interferon production were studied serially in humans after Herpes virus hominis (HSV) disease. Lymphocytes were isolated by filtration through a nylon fiber column and added to isologous macrophage cultures prepared 1 week previously. Macrophage-lymphocyte interaction was required for optimum interferon production. A selective increase in interferon production was associated with disease occurrence in some individuals. The increase in interferon production by lymphocytes was maximum between 2 and 6 weeks after disease. In contrast, lymphocyte transformation and serum antibody levels were similar throughout a 12-week period after disease and appeared to reflect prior immune status rather than acute infection. Some subjects with HSV disease failed to produce a detectable interferon response within the 2- to 6-week period after disease. In these individuals, lesion recurrence was more frequent when compared to subjects producing greater quantities of interferon after disease.