Mammalian 2-Cys peroxiredoxin (Prx) enzymes are overexpressed in most cancer tissues, but their specific signaling role in cancer progression is poorly understood. Here we demonstrate that Prx type II (PrxII) plays a tumor-promoting role in colorectal cancer by interacting with a poly(ADP-ribose) polymerase (PARP) tankyrase. PrxII deletion in mice with inactivating mutation of adenomatous polyposis coli (APC) gene reduces intestinal adenomatous polyposis via Axin/β-catenin axis and thereby promotes survival. In human colorectal cancer cells with APC mutations, PrxII depletion consistently reduces the β-catenin levels and the expression of β-catenin target genes. Essentially, PrxII depletion hampers the PARP-dependent Axin1 degradation through tankyrase inactivation. Direct binding of PrxII to tankyrase ARC4/5 domains seems to be crucial for protecting tankyrase from oxidative inactivation. Furthermore, a chemical compound targeting PrxII inhibits the expansion of APC-mutant colorectal cancer cells in vitro and in vivo tumor xenografts. Collectively, this study reveals a redox mechanism for regulating tankyrase activity and implicates PrxII as a targetable antioxidant enzyme in APC-mutation-positive colorectal cancer.2-Cys peroxiredoxin (Prx) enzymes are highly expressed in most cancers but how they promote cancer progression is unclear. Here the authors show that in colorectal cancers with APC mutation, PrxII binds to tankyrase and prevents its oxidative inactivation, thereby preventing Axin1-dependent degradation of ²b-catenin.