Background & Aims: This study aimed to determine the role of the RNA binding protein apobec-1 in radioprotection of the intestine. Methods: Apobec-1-deleted mice (APOBEC-1-/-) and wild-type controls were treated with 12 Gy of whole-body γ-irradiation in a cesium irradiator. The number of surviving intestinal crypts was assessed 3.5 days after irradiation by using a clonogenic assay. Cyclooxygenase-2 messenger RNA and protein expression were determined by real-time polymerase chain reaction and Western blot, respectively. RNA stability was studied by examining the turnover of a chimeric transcript containing the cyclooxygenase-2 3′ untranslated region cloned downstream of luciferase complementary DNA. Apobec-1 binding to the cyclooxygenase-2 3′ untranslated region was studied by electrophoretic mobility shift and UV crosslinking assays. Results: After γ-irradiation, the survival of intestinal stem cells decreased significantly in APOBEC-1 -/- mice. In wild-type mice treated with lipopolysaccharide before γ-irradiation, intestinal stem cells were protected by marked increases in prostaglandin E2 mediated by cyclooxygenase-2. No such effect was observed in the APOBEC-1-/- mice. The mechanism of this radioprotective effect involves the binding of apobec-1 to AU-rich sequences in the first 60 nucleotides of the 3′ untranslated region of cyclooxygenase-2. Upon binding to the AU-rich sequences, apobec-1 stabilizes cyclooxygenase-2 messenger RNA. This stabilization process does not seem to be mediated by p38 mitogen-activated protein kinase pathways. Conclusions: Lipopolysaccharide increases intestinal stem cell survival through apobec-1-mediated regulation of cyclooxygenase-2 messenger RNA stability.