Objectives: Peroxisome proliferator-activated receptor (PPAR) has been shown to be a protective transcription factor in mouse models of inflammatory bowel disease (IBD). PPAR is expressed in several different cell types, and mice with a targeted disruption of the PPAR gene in intestinal epithelial cells demonstrated increased susceptibility to dextran sodium sulfate (DSS)-induced IBD. However, the highly selective PPAR ligand rosiglitazone decreased the severity of DSS-induced colitis and suppressed cytokine production in both PPAR intestinal specific null mice and wild-type littermates. Therefore the role of PPAR in different tissues and their contribution to the pathogenesis of IBD still remain unclear. Methods: Mice with a targeted disruption of PPAR in macrophages (PPAR^M) and wild-type littermates (PPAR^F/F) were administered 2.5% DSS in drinking water to induce IBD. Typical clinical symptoms were evaluated on a daily basis and proinflammatory cytokine analysis was performed. Results: PPAR^M mice displayed an increased susceptibility to DSS-induced colitis in comparison to wild-type littermates, as defined by body weight loss, diarrhea, rectal bleeding score, colon length and histology. Interleukin (IL)-1, CCR2, MCP-1 and iNOS mRNA levels in colons of PPAR^M mice treated with DSS were higher than in similarly treated PPAR^F/F mice. Conclusions: The present study has identified a novel protective role for macrophage PPAR in the DSS-induced IBD model. The data suggest that PPAR regulates recruitment of macrophages to inflammatory foci in the colon.