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The increasing potential for radiation exposure from nuclear accidents or terrorist activities has intensified the need to develop pharmacologic countermeasures against injury from total body irradiation (TBI). Many initial experiments to develop and test these countermeasures utilize murine irradiation models. Yet, the route of drug administration can alter the response to irradiation injury. Studies have demonstrated that cutaneous injuries can exacerbate damage from radiation, and thus surgical implantation of osmotic pumps for drug delivery could adversely affect the survival of mice following TBI. However, daily handling and injections to administer drugs could also have negative consequences. This study compared the effects of subcutaneous needlesticks with surgical implantation of osmotic pumps on morbidity and mortality in a murine model of hematopoietic acute radiation syndrome (H-ARS). C57BL/6 mice were sham irradiated or exposed to a single dose of 7.7 Gy60Co TBI. Mice were implanted with osmotic pumps containing sterile saline seven days prior to irradiation or received needlesticks for 14 days following irradiation or received no treatment. All irradiated groups exhibited weight loss. Fewer mice with osmotic pumps survived to 30 days post irradiation (37.5%) than mice receiving needlesticks or no treatment (70% and 80%, respectively), although this difference was not statistically significant. However, mice implanted with the pump lost significantly more weight than mice that received needlesticks or no treatment. These data suggest that surgical implantation of a drug-delivery device can adversely affect the outcome in a murine model of H-ARS.