Cross-reactivity between type II collagen (CII) and C1q, the collagen-like subunit of the first component of complement, has been demonstrated in synovial fluid (SF) from rheumatoid arthritis (RA) patients. Many authors have studied autoimmunity to CII in RA, but little work has been done on autoimmunity to C1q in RA. In the data presented here, we have been able to show that in addition to native C1q, an altered form of C1q is present in SF from RA patients. Furthermore, a low molecular weight form of C1q is present in RA SF, although its role, if any, in the pathogenesis of RA is unclear. The presence in these RA SF of C1q-specific antibodies (IgG and IgM) has been studied and we have partially characterized the antibody moieties involved. As well as binding to C1q and fragments representing the collagen-tails from C1q, 7 S IgG autoantibodies against C1q also bind to a C1q molecule altered in vitro by incubation with reactive oxygen species and to the non-apeptide KGEQGEPGA (representing residues 26-34 from the C1q A-chain), which has previously been shown to suppress the onset of CII-induced arthritis in an animal model.