63 patients on long-term oral therapy with phenytoin sodium (sodium diphenylhydantoin) were screened for abnormalities of immunological function. They were compared with 92 controls and 28 patients with lymphoma. Depression of cellular or humoral immunity, or both, was found in a significant number of phenytoin-treated and lymphoma subjects. Phenytoin therapy was associated with low immunoglobulin A (21%), failure of antibody response to Salmonella typhi antigen (9%), absence of delayed hypersensitivity (D.H.S.) to three common skin-test antigens (22%), and depression of in-vitro lymphocyte transformation by phytohæmagglutinin (27%). Lymphoma patients manifested low IgM (22%), and inability to make antibody to S. typhi(11%) and to tetanus toxoid (21%). D.H.S. was absent in 36%; lymphocyte transformation was depressed in 17%. Abnormal lymphocyte transformation did not correlate with depression of cellular or humoral immunity in either group.