This study was designed to determine if poorly biodegradable bacterial cell wall components can produce chronic intestinal inflammation. A sterile aqueous suspension of sonically disrupted group A or group D streptococcal cell wall fragments was injected intramurally into the small intestine and cecum of 100 rats. Gross findings in rats killed at intervals of 1 day to 6 mo included intestinal thickening, adhesions, and mesenteric contraction. Acute histologic inflammation subsided by 2 wk, but chronic granulomatous inflammation persisted for 6 mo in the rats injected with group A streptococcal cell wall fragments and 3 mo in the rats injected with group D streptococcal cell wall fragments. Ninety-six control rats identically injected with human serum albumin or phosphate-buffered saline demonstrated mild acute inflammation that resolved, with only 1 rat having chronic intestinal inflammation. Granulomas in the intestine, mesentery, and mesenteric lymph nodes developed in 46% of the rats injected with group A fragments and 45% of the rats injected with group D streptococcal cell wall fragments, compared with 20% of the controls injected with albumin and 4% of the controls injected with phosphate-buffered saline. Group A streptococcal antigen was detected by immunofluorescence at the site of inflammation for 4 mo, and possible reactivation of acute inflammation was seen up to 6 mo after injection. We conclude that bacterial cell wall fragments are capable of producing chronic granulomatous inflammation in the intestinal wall if present in appropriate particle size and concentration. We speculate that cell walls from the enteric microflora may leak across a permeable mucosa in chronic inflammatory bowel disease to initiate and sustain local and systemic inflammation.