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Inflammatory bowel disease is characterized by chronic intestinal inflammatory disorders associated with increased risk of developing colorectal cancer. However, the detailed mechanisms are not fully understood. The aim of this study was to determine the effect of macrophage scavenger receptor class A1 (SR-A1), a pattern recognition receptor primarily expressed in macrophages, on colitis and clarify the underlying mechanisms. We found that SR-A1−/− mice had an aggravating dextran sodium sulfate-induced acute and recurring colitis. This action was associated with a robust activation of both canonical and noncanonical NF-κB signaling in the colon. Suppression of the noncanonical NF-κB signaling by SR-A1 may be via its interaction with TRAF3 in macrophages. Furthermore, the anti-inflammation effect of SR-A1 could inhibit occurrence of colitis-associated cancer in mice. These results, for the first time, demonstrate that SR-A1 as a suppressor for inflammatory bowel disease.