HLA-DR antigens and cellular sensitivity to native bovine type I and type II collagen and proteoglycans were examined in patients with classic rheumatoid arthritis (RA) and normal individuals. Fifty eight percent of patients with RA (n = 88) and 28% of normals (n = 52) were DR4+ (pc less than 0.01). DR4 phenotype was significantly increased in patients with severe disease stages (III-IV), as defined by the ARA criteria, in contrast to those showing mild disease stages (I-II) (p less than 0.05). Furthermore, peripheral blood mononuclear cells from 55 patients and 30 controls were evaluated for the in vitro production of leukocyte inhibitory factor in response to native type I and type II collagen and proteoglycans. By using this assay, cells from the arthritic group exhibited a statistically significant response when stimulated with native type I collagen and proteoglycans. The cellular immune response was not associated with any particular HLA-DR antigens, or to the disease stage or severity.