The induction of acute arthritis in rats by a single intraperitoneal injection of group A streptococcal cell wall is associated with the activation of complement. We have therefore investigated the interaction of arthropathic peptidoglycan-polysaccharide complex of streptococcal cell walls and human complement. The incubation of cell wall in normal human serum results in the formation of complexes of cell wall and the C3 and C4 components of complement. Using agammaglobulinemic serum, we have further shown that the activation of complement and formation of complement-cell wall complexes absolutely requires the presence of a small quantity of specific antibody. This antibody is present in normal human immunoglobulin G and is effective as the Fab fragment (alternative pathway). Although antibodies specific for three cell wall epitopes were capable of inducing complement-cell wall complex formation by the classical complement pathway, only anti-A polysaccharide antibody (N-acetyl-D-glucosamine epitope) was effective by the alternative complement pathway. A complement consumption assay showed that anti-cell wall antibody was required not only for complement-cell wall complex formation, but also for activation of complement by streptococcal cell wall in human serum. These studies suggest that a minimal level of anti-cell wall antibody may be required for the induction of arthritis in rats by streptococcal cell wall.