The peptidoglycan–polysaccharide (PGPS) model using inbred rats closely mimics Crohn's disease. Our aim was to identify mouse strains that develop ileocolitis in response to bowel wall injection with PGPS. Mouse strains studied included NOD2 knockout animals, RICK/RIP2 knockout animals, and genetically inbred strains that are susceptible to inflammation. Mice underwent laparotomy with intramural injection of PGPS or human serum albumin in the terminal ileum, ileal Peyer's patches, and cecum. Gross abdominal score, cecal histologic score, and levels of pro-fibrotic factor mRNAs were determined 20 to 32 days after laparotomy. PGPS-injected wild-type and knockout mice with mutations in the NOD2 pathway had higher abdominal scores than human serum albumin–injected mice. The RICK knockout animals tended to have higher mean abdominal scores than the NOD2 knockout animals, but the differences were not significant. CBA/J mice were shown to have the most robust response to PGPS, demonstrating consistently higher abdominal scores than other strains. Animals killed on day 26 had an average gross abdominal score of 6.1 ± 1.5, compared with those on day 20 (3.0 ± 0.0) or day 32 (2.8 ± 0.9). PGPS-injected CBA/J mice studied 26 days after laparotomy developed the most robust inflammation and most closely mimicked the PGPS rat model and human Crohn's disease.