Inflammation occurs in the context of integrin-mediated adhesive interactions of cells with their extracellular matrix environment. We investigated the role of the collagen binding integrin α1β1 in a model of colitis. α1β1 was expressed on lamina propria T cells and monocytes during disease. Both α1 deficiency and anti-α1 mAb treatment (prophylactic and therapeutic) protected against colitis. In vivo α1β1 blockade improved macroscopic and histologic scores, decreased inflammatory cytokine production, and profoundly affected the ability of lamina propria mononuclear cells to proliferate and produce IFN-γ in vitro. Development and α1-mediated inhibition of colitis can be lymphocyte independent, suggesting that activated monocytes also represent a key α1β1-expressing cell type involved in colitis. These results underscore the importance of innate immunity and, specifically, of leukocyte/matrix interactions in regulating local inflammatory responses.