Peripheral blood mononuclear cells from 46 systemic lupus erythematosus (SLE) patients showed reduced ability to proliferate in vitro in response to the soluble antigen, tetanus toxoid, as compared with 96 normal controls. Special studies of 27 untreated SLE patients also revealed significantly decreased blastogenic responses to tetanus toxoid. In both the total and untreated SLE populations, decreased mean tetanus antibody titers also were found as compared with the control population. However, the reduction in antibody titer and blastogenic response was not strictly parallel. A limited immunization program was initiated in low-responding volunteers from the SLE and normal populations. Three out of four SLE patients did not develop a significant blastogenic response despite increases in anti-tetanus titers after immunization, whereas all normals showed significant increases in both blastogenic and antibody responses. The accumulated evidence indicated that the unresponsiveness was the result of a defect in T-cell function. Monocyte reactivity was demonstrated to be normal, and no evidence was found for the presence of suppressor cells, inhibition by immune complexes, or increased prostaglandins to explain the defect.