Traumatic brain injury (TBI) in children is associated with high rates of morbidity and mortality. Nosocomial respiratory infections are common following severe TBI, especially with polytraumatic TBI. Although post-injury immunosuppression has been identified as a potential contributor to nosocomial infection, the underlying mechanism and optimal therapy are poorly understood. In this study, we used a combined model of TBI plus extra-cranial hemorrhage followed by intranasal inoculation with Streptococcus pneumoniae to model the clinical scenario of polytrauma TBI and post-injury infection. Briefly, 28-day (prepubescent) rats received either sham injury or prefrontal controlled cortical impact injury plus removal of 25% of blood volume through femoral cannulation. Saline or 50µg/kg granulocyte-macrophage colony-stimulating factor (GM-CSF) was administered intraperitoneally daily for 2 days. Post-injury immune response was assessed in the blood, spleen, and brain using different immunologic techniques, while bacterial clearance was examined by plating lung tissue. Our results show that GM-CSF enhanced innate immune function by increasing the percentage of blood monocytes expressing elevated levels of MHC II molecules. GM-CSF also significantly increased splenic CD3 + T-cells, compared to the saline-treated injury group. Moreover, increased lung bacterial load (colony-forming units) was significantly reduced with GM-CSF treatment. Treatment with GM-CSF was not associated with an increase in brain glial activation, neuronal loss, or memory dysfunction. This study highlights the potential role of GM-CSF as a therapy to address the increased risk of nosocomial infections following polytraumatic TBI.