Rabbits treated with phenytoin in various ways, were immunized with human serum or with sheep erythrocytes. The antibody response in rabbits injected with the antigen mixed with phenytoin differed distinctly from the response obtained in animals having received the antigen alone or mixed with diluent. The effect of phenytoin on the antibody response depended on the nature of the antigen. The response to some antigens was suppressed, to some potentiated, and to some potentiated in the early phase and then suppressed. The effect comprised both IgM and IgG responses. Skin hypersensitivity tests did not reveal any effect on the cellular immune response. These findings may explain why particularly IgA is affected in patients taking phenytoin by the oral route, and why either reduction or elevation of IgA may occur.