C-Reactive protein (CRP) is the prototypic acute-phase serum protein in man. On the basis of its binding specificities and activities, it has been proposed that CRP facilities the removal of nuclear material released from damaged cells. To determine whether such a process could alter the development of autoimmunity to nuclear antigens, the effect of CRP on autoimmune disease in the (NZB x NZW) F1 mouse model of systemic lupus erythematosus was tested. Mice were injected with chromatin bound to latex beads in the presence or absence of bound CRP. CRP treatment significantly prolonged survival of mice injected with chromatin-coated beads. CRP also produced a transient decrease in IgG antibody levels to histones, DNA, and DNP, suggesting a general suppressive effect on ongoing antibody responses. To determine whether CRP would affect chromatin clearance, the effect of CRP on nucleosome core particle clearance was tested in BALB/c mice. CRP pretreatment did not alter the rate of clearance or organ localization of nucleosome core particles. These findings indicate that CRP can modify the course of autoimmune disease possibly by preventing the exposure of nuclear antigens to the immune system.