Tumor necrosis factor α (TNF-α) is an important mediator of programmed cell death, and TNF-α blockade significantly improves disease severity in several inflammatory conditions, including Crohn's disease (CD), one of the idiopathic inflammatory bowel diseases. However, the precise mechanism(s) of action of anti-TNF-α therapy in CD remains poorly understood. SAMP1/YitFc mice develop a spontaneous ileitis with similarities to human CD in regard to histological features as well as response to conventional treatments. In this report, we tested the novel hypothesis that the beneficial effects of anti-TNF-α therapy in CD are mediated by a mechanism that involves down-regulation of intestinal epithelial cell (IEC) apoptosis. Similar to the efficacy of monoclonal anti-TNF-α antibodies in human CD, a single injection of a chimeric anti-murine TNF-α antibody into SAMP1/YitFc mice resulted in a marked suppression of intestinal inflammation and epithelial cell damage compared with mice injected with an isotype control antibody. These effects were associated with a significant reduction in apoptosis of freshly isolated IEC as assessed by propidium iodide staining and DNA laddering. In contrast, an increase in lamina propria mononuclear cell apoptosis was observed in anti-TNF-α-treated mice compared with control. These results were confirmed in vivo by using the terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling-assay. In addition, neutralization of TNF-α reduced membrane bound FAS/CD95 expression in IEC from SAMP1/YitFc mice compared with control antibody. These data demonstrate a novel mechanism of action of anti-TNF-α therapy that involves homeostatic regulation of mucosal cell apoptosis, which results in the net decrease of chronic inflammation typically found in CD.