Antibodies to the collagen-like region of C1q have recently been observed in sera of patients with systemic lupus erythematosus (SLE). In this study, we documented that these antibodies were present in 47.3% of SLE patient sera, whereas they were uncommon in sera from patients with rheumatoid arthritis (2.8%) and Sjögren's syndrome (12.8%), as well as in normal sera (6.4%). Markedly elevated antibody levels (greater than 4 SD above the normal mean) were observed almost exclusively in sera of patients with SLE. Levels of antibodies to the collagen-like region correlated highly with levels of solid-phase C1q-binding IgG when analyzed by the C1q solid-phase assay for immune complexes (r = 0.87). We previously found that, after sucrose density gradient ultracentrifugation, a predominance of the solid-phase C1q-binding IgG in SLE sera sediments as monomeric IgG. These findings, together with the present data, indicate that reactivity of SLE patients' sera in the C1q solid-phase assay reflects primarily the presence of antibodies to the collagen-like region, and not the presence of immune complexes.