The role of gammadelta T cells in inflammatory bowel disease (IBD) is still controversial. Although gammadelta T cells induce IBD in immunodeficient animals, others suggest a protective role of gammadelta T cells. Therefore, this study was conducted in order to elucidate the effect of gammadelta T cell depletion/deficiency on different IBD animal models. Mice depleted of or deficient in gammadelta T cells were exposed to dextran sodium sulfate (DSS) in order to induce colitis. In addition, gammadelta T cells were depleted in mice with terminal ileitis (TNFDeltaARE) or colitis due to interleukin 2 deficiency (IL-2 ko). Finally, DSS-induced colitis was studied in mice deficient in interferon gamma (IFN-gamma ko) upon gammadelta T cell depletion. Depletion of gammadelta T cells aggravated DSS-induced colitis and terminal ileitis of TNFDeltaARE mice. Exacerbated DSS-induced colitis was also found in gammadelta T cell-deficient mice. IL-2 ko mice showed increased mortality upon early (starting at 4 wk of age) but not late depletion (starting at 8 wk of age). Early gammadelta T cell depletion or deficiency resulted in increased IFN-gamma production by both lamina propria lymphocytes and splenocytes in every model investigated herein. In IFN-gamma ko mice, gammadelta T cell depletion did not affect the development and course of DSS-induced colitis. The protective effect of gammadelta T cells in IBD was confirmed in various IBD animal models. Particularly, during the early phase of intestinal inflammation, gammadelta T cells appear to be important. The mechanism seems to involve the control of IFN-gamma production and epithelial regeneration.