The aim of the present study was to elucidate the beneficial effects of rosuvastatin, a new HMG-CoA reductase inhibitor, on colonic mucosal damage and on the inflammatory response in a dextran sulfate sodium (DSS) colitis model. Acute colitis was induced using 8% DSS in female BALB/c mice. Colonic mucosal inflammation was evaluated clinically, biochemically, and histologically. Mucosal protein contents and mRNA levels of tumor necrosis factor (TNF)-alpha were determined by immunoassay and real time-PCR. The mRNA levels of endothelial nitric oxide synthase (eNOS) were determined by real-time PCR. Disease activity scores in DSS-induced colitis model mice, as determined by weight loss, stool consistency, and blood in stool, were significantly lower in the rosuvastatin-treated mice than in control mice. Shortening of the colon was significantly reversed by rosuvastatin. Increases in tissue-associated myeloperoxidase activity and thiobarbituric acid-reactive substances after DSS administration were both significantly inhibited by treatment with rosuvastatin. Rosuvastatin also inhibited increases in intestinal TNF-alpha protein and mRNA expression after DSS administration, respectively. The mucosal mRNA levels of eNOS were decreased after DSS administration, but preserved in mice treated with rosuvastatin. These results suggest that rosuvastatin prevents the development of DSS-induced colitis in mice via the inhibition of mucosal inflammatory responses associated with the preservation of eNOS transcription.