NLR family apoptosis inhibitory proteins (NAIPs) belong to both the Nod-like receptor(NLR) and the inhibitor of apoptosis (IAP) families. NAIPs are known to form an inflammasomewith NLRC4, but other in vivo functions remain unexplored. Using mice deficient forall NAIP paralogs (Naip1-6Δ/Δ), we show that NAIPs are key regulators of colorectal tumorigenesis.Naip1-6Δ/Δ mice developed increased colorectal tumors, in an epithelial-intrinsicmanner, in a model of colitis-associated cancer. Increased tumorigenesis, however, was notdriven by an exacerbated inflammatory response. Instead, Naip1-6Δ/Δ mice were protectedfrom severe colitis and displayed increased antiapoptotic and proliferation-related geneexpression. Naip1-6Δ/Δ mice also displayed increased tumorigenesis in an inflammationindependentmodel of colorectal cancer. Moreover, Naip1-6Δ/Δ mice, but not Nlrc4-nullmice, displayed hyper-activation of STAT3 and failed to activate p53 18 h after carcinogenexposure. This suggests that NAIPs protect against tumor initiation in the colon by promotingthe removal of carcinogen-elicited epithelium, likely in a NLRC4 inflammasomeindependentmanner. Collectively, we demonstrate a novel epithelial-intrinsic function ofNAIPs in protecting the colonic epithelium against tumorigenesis.