Combined radiation and burn injuries are likely to occur after nuclear events, such as a meltdown accident at a nuclear energy plant or a nuclear attack. Little is known about the mechanisms by which combined injuries result in higher mortality than by either insult alone, and few animal models exist for combined radiation and burn injury. Herein, the authors developed a murine model of radiation and scald burn injury. Mice were given a single dose of 0, 2, 4, 5, 6, or 9 Gray (Gy) alone, followed by a 15% TBSA scald burn. All mice receiving ≤4 Gy of radiation with burn survived combined injury. Higher doses of radiation (5, 6, and 9 Gy) followed by scald injury had a dose-dependent increase in mortality (34, 67, and 100%, respectively). Five Gy was determined to be the ideal dose to use in conjunction with burn injury for this model. There was a decrease in circulating white blood cells in burn, irradiated, and combined injury (5 Gy and burn) mice by 48 hours postinjury compared with sham (49.7, 11.6, and 57.3%, respectively). Circulating interleukin-6 and tumor necrosis factor-α were increased in combined injury at 48 hours postinjury compared with all other treatment groups. Prolonged overproduction of proinflammatory cytokines could contribute to subsequent organ damage. Decreased leukocytes might exacerbate immune impairment and susceptibility to infections. Future studies will determine whether there are long lasting consequences of this early proinflammatory response and extended decrease in leukocytes.