Exposure of the gastrointestinal (GI) tract to high doses of radiation can lead to lethality from the GI syndrome. Although the molecular mechanism regulating the GI syndrome remains to be fully defined, we have recently demonstrated that p53 within the GI epithelial cells controls the radiation-induced GI syndrome. Mice lacking p53 in the GI epithelium were sensitized to the GI syndrome, while transgenic mice with one additional copy of p53 called “Super p53” mice were protected from the GI syndrome. Here, we crossed Super p53 mice to p21^–/– mice that lack the cyclin-dependent kinase inhibitor p21. Super p53; p21^–/– mice were sensitized to the GI syndrome compared to Super p53 mice that retain one p21 allele. In addition, mice lacking p21 were not protected from the GI syndrome with one extra copy of p53. These results suggest that p21 protects Super p53 mice from the GI syndrome.