The effect of heat-aggregated human gamma globulin (aggFII) on the induction of in vitro lymphocyte transformation, measured by the uptake of tritiated thymidine into newly synthesized DNA, was studied with peripheral blood lymphocytes derived from 12 patients with rheumatoid arthritis (RA), six with ankylosing spondylitis (AS), two with systemic lupus erythematosus (SLE), and seven normal subjects. It was found that 200 μg aggFII induced significant transformation of the lymphocytes of eight patients with RA, five with AS, one with SLE, and one normal subject. Neither deaggregated FII nor heat-aggregated human serum albumin induced significant transformation of the lymphocytes of any subject tested. A source of complement appeared necessary to support aggFII-induced blastogenesis, since enhanced transformation occurred only in the presence of fresh plasma. Heat-inactivated plasma and fetal calf serum (FCS), and FCS devoid of hemolytic complement, failed to support enhanced blastogenesis in the presence of aggFII. Since substrates similar to those employed in these studies are present in vivo in the rheumatoid joint, it is suggested that aggFII may enhance intra-articular lymphocyte transformation in subjects with RA.