The mixed leukocyte reaction (MLR) responses of 29 patients with classic rheumatoid arthritis (RA) were compared with those of 24 age-and sex-matched healthy controls. Pools of stimulating cells were selected to include the major cross-reacting HL-A specificities. In pooled human serum the MLR response of the RA lymphocytes was significantly enhanced relative to the response controls (P < 0.05). In autologous serum there was suppression of the MLR response in patients with RA which correlated with disease activity. The data suggest the presence of an intrinsically enhanced cellular reactivity of RA lymphocytes suppressed by serologic factor(s). The mechanisms of this enhancement of suppression are discussed.