The lymphocyte response to antigen of Staphylococcus aureus was examined in 67 uninfected diabetic subjects and in 71 age-matched subjects who were not diabetic. Peripheral blood lymphocytes were exposed to phytohemagglutinin and to antigen of S. aureus in triplicate cultures in the lymphocyte transformation assay. Diabetic subjects including those who were in good metabolic control had significantly decreased responses to staphylococcal antigen (P less than 0.05) but not to phytohemagglutinin. The use of fetal calf serum in place of autologous plasma in the nutrient medium did not correct the defect. Lymphocytes from normal subjects were cultured in diabetic plasma as well as in autologous plasma; the differences were not significant. These findings indicate that diabetic persons have an impaired response to staphylococcal antigen, a defect which appears to be in the lymphocyte itself and not in the serum factor.