Depression of one or more parameters of cellular and/or humoral immune responses was found in 60% of general hospital patients treated with phenytoin and 47% of patients treated with carbamazepine. Phenytoin-treated patients failed to manifest delayed hypersensitivity (DHS) reactions to common antigens, and to make antibody to Salmonella typhi and tetanus toxoid. Serum levels of IgA and IgM, DNA synthesis in circulating leucocytes, and phytohaemagglutinin (PHA) induced deoxyribonucleic acid synthesis were also low. Depression of IgA, DHS reactivity and antibody responsiveness to S. typhi were shown to develop after the commencement of phenytoin therapy in a study of eleven patients. The presence of immunological defects was independent of the dosage of drug, its serum concentration, the duration of therapy and the sex of the subject. Studies in vitro provided evidence that immunosuppression was the result of a direct effect of phenytoin on the metabolism of lymphoid cells. Carbamazepine was shown to have a similar but less potent direct effect. Pharmacological concentrations of phenytoin caused a significant depression of DNA synthesis in PHA-stimulated and non-stimulated blood cell cultures in vitro. High concentrations in addition caused depression of cell counts, lymphocyte blastogenesis, ribonucleic acid and protein synthesis. Phenytoin was not cytocidal at concentrations of up to 125 mug/ml. Depression of DNA synthesis by phenytoin was maximal when phenytoin was added within 4-8 hr of the addition of PHA. PHA-induced DNA synthesis was not significantly affected by pre-incubation with phenytoin. In vivo, the presence of immunological defects was not related to phenytoin-induced folic acid deficiency. High concentrations of carbamazepine, but not phenobarbitone or diazepam caused a significant depression of PHA-stimulated DNA synthesis in blood cell cultures. The data show that immunosuppression is a common side-effect of phenytoin therapy, and that lymphoma is rare. They suggest that in the presence of phenytoin-induced immunosuppression another factor, or factors are required to induce the formation of lymphoma.