We have investigated the presence of autoantibodies to the collagen-like region (CLR) of C1q and its relationship with classical pathway-dependent hypocomplementemia in patients with SLE. Antibodies to CLR/C1q were quantitated in the plasma of 113 unselected patients with SLE by ELISA, using purified CLR as antigen. Plasma concentration of C3, CH50 activity and C2 hemolytic activity were determined according to standard procedures. The prevalence of IgG antibodies to CLR/C1q in the study population was 33.6%. Plasma titers of anti-CLR/C1q autoantibodies showed a strong negative correlation with CH50 activity (p < 0.0001) and with plasma levels of C3 (p < 0.0001). Eighty-five percent of patients with severe complement consumption exhibited high titers of anti-CLR/C1q antibodies in plasma, independently of clinical disease activity. Anti-CLR/C1q antibodies were present in the plasma of 38% of patients with moderate classical pathway consumption and 14% of patients with no evidence of complement consumption. Analysis of sequential samples from six patients over a period of 18 to 24 months demonstrated that changes in CH50 activity mirrored those of the plasma titers of anti-CLR/C1q antibodies. Acquired hypocomplementemia through the classical pathway is strongly associated with the presence of anti-CLR/C1q autoantibodies in SLE. The results suggest that anti-CLR/C1q antibodies may perpetuate classical pathway activation, independently of clinical disease activity.