Cell wall polymers isolated from group A streptococci, as well as lipopolysaccharide from Salmonella typhimurium and synthetic muramyl dipeptide, were injected into the ankle joints of rats. The inflammatory responses were assessed by gross and histologic examination, and edema was measured by accumulation of radiolabeled albumin in the limbs. The isolated group-specific polysaccharide induced extensive edema of the articular and periarticular tissue immediately after injection, and this resolved in 24 hours. The peptidoglycan moiety did not produce early edema, but induced an acute exudative reaction followed by a proliferative synovitis which resolved after 5 days. Reactions induced by covalently bound complexes of peptidoglycan and the group-specific polysaccharide (PG-APS) varied, depending on the size of the complex. Small fragments, derived from mutanolysin digestion, caused both an acute edematous reaction and transient arthritis. Larger fragments did not cause the immediate edematous reaction, but induced an acute arthritis that appeared within 24 hours and evolved into a chronic process. Episodes of recurrent inflammation, a distinctive feature of joint inflammation induced by systemic injection of PG-APS polymers, were not observed following intraarticular injection of any of the cell wall polymers. The relative susceptibility of different rat strains to arthritis induced by intraarticular injection paralleled the responses to systemic injection of PG-APS. These results demonstrate that variations in arthropathogenicity are due, in part, to inherent differences in the phlogistic activities of different cell wall polymers, and that the genetic control of susceptibility involves regulation of the inflammatory responses rather than the quantity of cell wall distributed to the joint.