Exposure to ionizing irradiation may affect brain functions directly, but may also change tissue sensitivity to a secondary insult such as trauma, stroke, or degenerative disease. To determine if a low dose of particulate irradiation sensitizes the brain to a subsequent injury, C56BL6 mice were exposed to brain only irradiation with 0.5 Gy of 56Fe ions. Two months later, unilateral traumatic brain injury was induced using a controlled cortical impact system. Three weeks after trauma, animals received multiple BrdU injections and 30 days later were tested for cognitive performance in the Morris water maze. All animals were able to locate the visible and hidden platform during training; however, treatment effects were seen when spatial memory retention was assessed in the probe trial (no platform). Although sham and irradiated animals showed spatial memory retention, mice that received trauma alone did not. When trauma was preceded by irradiation, performance in the water maze was not different from sham-treated animals, suggesting that low-dose irradiation had a protective effect in the context of a subsequent traumatic injury. Measures of hippocampal neurogenesis showed that combined injury did not induce any changes greater that those seen after trauma or radiation alone. After trauma, there was a significant decrease in the percentage of neurons expressing the behaviorally induced immediate early geneArcin both hemispheres, without associated neuronal loss. After combined injury there were no differences relative to sham-treated mice. Our results suggest that combined injury resulted in decreased alterations of our endpoints compared to trauma alone. Although the underlying mechanisms are not yet known, these results resemble a preconditioning, adaptive, or inducible-like protective response, where a sublethal or potentially injurious stimulus (i.e., irradiation) induces tolerance to a subsequent and potentially more damaging insult (trauma).