A deficiency in understanding the steps responsible for colitis is the lack of comprehension for the role chemokines play in mucosal inflammation. IFN-γ-inducible protein-10 (IP-10) and CXCR3 are highly expressed at sites of colitis. Our findings show that IP-10 significantly contributes to the development of Th1 and inflammatory responses. Specifically, IP-10 inhibition in IL-10−/− mice attenuates the associated increases in serum and/or local amyloid A, IL-2, IL-6, TNF-α, IFN-γ, IL-1α, and IL-1β with colitis as compared with IL-10−/− mice that develop colitis similar to human Crohn’s disease. Correspondingly, the rate or intensity of inflammation in IL-10−/− mice treated with anti-IP-10 Abs showed improved scoring of inflammation, compared with control IL-10−/− mice. This study provides important and novel information regarding IP-10 as a target for the treatment of colitis.