Significance Excessive apoptosis is detected in the intestinal epithelium of patients with inflammatory bowel disease (IBD), where it is frequently TNF-dependent. We show that A20, a protein implicated in negative regulation of NF-κB, is expressed in intestinal epithelial cells (IECs) from patients with IBD in areas that exhibit apoptosis. Transgenic mice that overexpress A20 in IECs are highly susceptible to TNF-induced cell death. In these mice, A20 potentiates TNF-induced mucosal erosion and RIPK1-dependent IEC apoptosis through Ripoptosome/RIPK1 activation. A20-enhanced IEC damage and intestinal inflammation can be prevented by RIPK1 inhibitors, suggesting a new approach to IBD treatment.