In this study, 26 patients with rheumatoid arthritis (RA), 10 with gout, 8 with scleroderma and 10 healthy volunteers were included. Antibodies to native and denatured human collagen types I, II and III were measured by an enzyme linked immunosorbent assay (ELISA). The frequencies of antibodies to native collagen type II were 19% in the sera of 26 patients with RA. These antibodies were also cross-reacted with collagen types I and III and generally, their activities to collagen in synovial fluids were higher than that in the serum. Only one in 8 patients with scleroderma showed high serum antibodies to these collagens. However, levels of collagen antibodies in patients with RA were not correlated with levels of rheumatoid factor, IgG, IgM and IgA. There was no different in the interleukin (IL)-1 production by synovial cells stimulated by collagens from patients with either RA or gout. The correlation between anti-collagen antibodies and HLA-DR4 antigen was poor, though the presence of DR4 was common in patients with RA. These evidences suggest that collagen antibodies were important to joint pathology only in some of the patients with RA. Thus, collagen autoimmunity warrants further investigation.