Somatostatin analogs ameliorate intestinal injury after localized irradiation. This study investigated whether SOM230, a novel, metabolically stable analog with broad receptor affinity, reduces intestinal injury and lethality in mice exposed to total-body irradiation (TBI). Male CD2F1 mice were exposed to 7-15 Gy TBI. Twice-daily administration of SOM230 (1, 4 or 10 mg/kg per day) or vehicle was started either 2 days before or 4 h after TBI and continued for either 14 or 21 days. Parameters of intestinal and hematopoietic radiation injury, bacterial translocation, and circulating cytokine levels were assessed. Animal survival was monitored for up to 30 days. SOM230 increased survival (P < 0.001) and prolonged survival time (P < 0.001) whether administration was initiated before or after TBI. There was no benefit from administration for 21 compared to 14 days. The survival benefit of SOM230 was completely reversed by co-administration of pancreatic enzymes (P = 0.009). Consistent with the presumed non-cytoprotective mechanism of action, SOM230 did not influence hematopoietic injury or intestinal crypt lethality. However, SOM230 preserved mucosal surface area (P < 0.001) and reduced bacterial translocation in a dose-dependent manner (P < 0.001). Circulating IL-12 levels were reduced in SOM230-treated mice (P = 0.007). No toxicity from SOM230 was observed. SOM230 enhances animal survival whether administration begins before or after TBI; i.e., it is effective both as a protector and as a mitigator. The mechanism likely involves reduction of intraluminal pancreatic enzymes. Because of its efficacy and favorable safety profile, SOM230 is a promising countermeasure against radiation and should undergo further development.