Purpose: Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract with a poorly understood pathogenesis. Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) potently regulates the immune system through the activation of PAC1 (Trends Mol Med, 2003, p. 211–7), however, the role of PACAP and its receptor, PAC1, in inflammatory colitis is unclear. The purpose of this study is to elucidate the role of PACAP and its receptor, PAC1, in an experimental mouse model of colitis. Methods: Colitis was induced in 8 adult PAC1 +/+ and 7 PAC1 −/− mice with 2.5% DSS given orally for 6 days. Measurements of water and food intake, body weight, observations of mice activity and stool appearance were made at baseline and daily thereafter for six consecutive days. On the 7th day the intact colon from both groups of mice were dissected and examined macroscopically and microscopically to determine the degree of ulceration that was scored in a blinded fashion. Results: PAC1 −/− and PAC1 +/+ mice, both showed significant body weight loss following treatment with DSS. PAC1-/- mice showed a slightly lower, but statistically insignificant, intake of food (7.7 ± 5.47 g/day vs 9.5 ± 7.31 g/day) and water (11.89 ± 13.4 g/day vs 16.0 ± 14.70 g/day), compared to the PAC1 +/+ group. Using a macroscopic score scale with a maximum of 8 and a minimum of 0, the PAC1-/- mice had a higher macroscopic score (3 ± 0 vs 0 ± 0, p < 0.05, n = 15), compared to the wild type. A score of 0 indicates a normal colon, whereas a 3 indicates a colon with inflammation, ulcer (< 2cm), and colonic wall thickening. The colonic length to weight ratio was lower (29.07 ± 10.02 vs 14.86 ± 2.60, p = 0.013) in the PAC1 −/− mice, indicating a higher level of inflammation compared to the wild type group. The H and E stained slides of the distal and proximal confirmed that in the PAC1-/- group, a dense mucosal infiltrate, containing neutrophils, lymphocytes and macrophages, was significantly more abundant than in the PAC1 +/+ group. Conclusions: PAC1 receptor deficient mice exhibited significantly higher levels of colonic inflammation. These data suggests that the PAC1 receptor plays a protective role against colonic inflammation in mice, and may have the potential to help design future studies for treatment, and or, prevention of IBD.