Antibodies to human native and denatured types I, 11, 111, IV, and V collagens were measured using Iz5I-radioimmunoassay. Mean levels of binding by sera from 30 rheumatoid arthritis patients were significantly higher than those from 20 normal subjects against all of the collagens tested. The relative antibody concentration was higher in synovial fluid than in simultaneously obtained serum. Many patients with gout or various other rheumatic diseases also had detectable anticollagen antibodies. With a few notable exceptions, the majority of the reactivity detected in all patient groups was directed against covalent structural determinants present on all of the denatured collagens, suggesting a secondary reaction to tissue injury.A potential role for collagen autoimmunity in the pathogenesis of rheumatoid arthritis (RA) was suggested by Steffen in 1970 (1). Subsequently, several reports of antibodies to collagen in human sera and synovial fluid have appeared describing a variety of methods and reaching varied conclusions (2-6). Some authors have found frequent collagen reactivity in RA sera o r synovial fluid (2,5), while others have concluded that anomalous reactions could account. for the majority of reactivity (7-9). In addition, antibodies to collagen have been found in other diseases (10-12), raising some question as to the pathologic significance of antibodies to collagen in RA if they were present.Recently it was discovered that immunization of rats or mice with native type I1 collagen results in the development of an inflammatory polyarthritis (13). Arthritis was associated with both cellular and humora1 immunity to type I1 collagen (14). Because of this discovery, there has been renewed interest in the role of collagen autoimmunity in human arthritis. We have recently shown that type I1 collagen-induced arthritis in rats can be passively transferred with serum and that purified IgG anticollagen antibodies are capable of inducing arthritis in non-immunized rats ( I 5). During the course of our studies of collagen-induced arthritis in rats, we used a sensitive radioimmunoassay to detect antibodies to collagen (16). We now report on the application of that method in human arthritis.