Decreased serum folate (FA) levels were detected in 71% of 51 patients with rheumatoid arthritis (RA). Of 11 patients studied more intensively, only one fulfilled the usual hematologic criteria for FA deficiency. All, however, demonstrated an abnormally rapid plasma clearance of tritium-labeled pteroylglutamic acid (3HPGA). "Binding" of 3HPGA was evaluated by dialysis to apparent equilibrium and found to be significantly reduced in the sera of patients with RA. Common to all these patients was the ingestion of aspirin (ASA). Four RA patients not taking ASA had normal 3HPGA "binding". The 3HPGA "binding" of RA sera decreased as these patients were given increased ASA dosage and vice versa. The in vitro addition of ASA to normal sera reduced "binding" to the level detected in RA sera. Progressive increases in ASA resulted in progressive decreases in "binding". Aspirin given to three normal subjects reduced 3HPGA "binding" in all and serum FA in two. Precedents for ASA-induced structural change in binding proteins and for the relation between decreased binding and lowered serum levels are discussed. It is suggested that the low serum FA concentration and rapid plasma clearance of 3HPGA in RA might reflect ASA-induced alterations of FA binding, resulting in a redistribution rather than deficiency of this vitamin.