Inflammatory bowel disease is a quite severe chronic inflammation, treated mainly by immunosuppression, which often has serious side effects. As CD44 is important in lymphocyte activation and migration, we asked whether Abs against CD44 isoforms influence trinitrobenzenesulfonic acid (TNBS)-induced colitis in mice. A lethal colitis (73/111 mice) could be prevented in 69 of 97 mice by anti-CD44v7 (CD44 variant isoform v7), whereas anti-CD44s (CD44 standard isoform) and anti-CD44v6 had no effect. Upon receiving anti-CD44v7 after the disease had been fully exacerbated,> 90% of the mice recovered. TNBS plus anti-CD44v7-treated mice developed early signs of inflammation, with infiltration of leukocytes in the lamina propria and increased IFN-γ production. However, while control mice developed a severe pancolitis, the intestine fully regenerated in anti-CD44v7-treated mice. Locally and systemically, a strong increase in IL-10 production was noted. Thus, anti-CD44v7 can be regarded as a highly efficient and specific therapeutic reagent in chronic colitis, which probably functions by regulating an overshooting Th1 reaction.