Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple organ involvement, production of a wide range of autoantibodies and by formation and tissue deposition of immune complexes in the inflamed organs. In contrast to most systemic inflammatory conditions, and despite raised levels of pro-inflammatory cytokines, SLE flares are rarely reflected by elevated C-reactive protein (CRP), an important acute-phase reactant in man with homologues in vertebrates and several invertebrates. Normally, the circulating concentration of liver-derived CRP rises rapidly in response to infections and tissue injury, and CRP measurement is widely employed as a marker of ongoing inflammation. With sensitive methods, detection of small elevations of CRP is also valuable as a prognostic marker in cardiovascular disease. As a part of the innate immune system, CRP binds certain molecules exposed on the surface of dying cells/apoptotic bodies and on the surface of pathogens and mediates their elimination by uptake in the reticuloendothelial system. CRP also interacts with IgG-containing immune complexes, binds Fc-receptors and activates the complement system via C1q. In murine lupus, CRP has been found to decrease autoantibody levels and increase the survival rates. In this review we discuss possible explanations for, and consequences of, the relative CRP failure in SLE, as well as pathogenetic implications of anti-CRP autoantibodies.