C entral to inflammatory responses are the integrin-mediated adhesive interactions of cells with their ECM-rich environment. We investigated the role of the collagen-binding integrin α₁β₁ in intestinal inflammation using the mouse model of colitis induced by dextran sodium sulfate (DSS). mAb’s directed against murine α₁ were found to significantly attenuate inflammation and injury in DSS-treated wild-type mice; similar protection was seen in mice deficient for α₁β₁ integrin. Blockade or loss of α₁β₁ was also associated with decreased mucosal inflammatory cell infiltrate and cytokine production. Importantly, we demonstrated that development and α₁-mediated inhibition of DSS-induced colitis occurred independently of lymphocytes (Rag-2^–/– mice), and identified the monocyte as a key α₁β₁-expressing cell type involved in the development of colitis in this model. In response to DSS, both α₁ deficiency and anti-α₁ mAb treatment significantly reduced monocyte accumulation and activation within the lamina propria. In summary, the data demonstrate that engagement of leukocyte-associated α₁β₁ receptors with ECM plays a pivotal role in mediating intestinal inflammation via promotion of monocyte movement and/or activation within the inflamed interstitium. Therapeutic strategies designed to disrupt such interactions may prove beneficial in treating intestinal inflammation.