Apolipoprotein E (ApoE) plays an important role in lipid metabolism and neuronal repair. In humans, there are three major apoE isoforms: apoE2, apoE3 and apoE4. Compared to apoE3, apoE4 increases the risk to develop Alzheimer's disease, particularly in women, and of developing cognitive impairments after specific environmental challenges. ApoE isoform might also be a determinant of cognitive injury after cranial ⁵⁶Fe irradiation. To assess this possibility, in this study female apoE2, apoE3 and apoE4 mice were cranially irradiated with ⁵⁶Fe particles (600 MeV, 0, 1 or 2 Gy) and behaviorally tested 3 months later. Exploratory activity and measures of anxiety were also assessed as they can affect performance on cognitive tests. There were no effects of irradiation on exploratory activity or measures of anxiety in the open field or elevated zero maze. However, there were dose- and apoE isoform-dependent effects of irradiation on novel object recognition and spatial memory retention in the water maze. Compared to apoE2 and apoE3 mice, apoE4 mice were more sensitive to 2 Gy induced impairments in hippocampus-dependent spatial memory retention in the water maze after training to locate the first hidden platform location, but less sensitive to 2 Gy induced cortical impairments in novel object recognition. Conversely, of the irradiated mice, apoE4 mice irradiated with 1 Gy were the only group of mice that showed spatial memory retention for the second platform location after reversal learning in the water maze. Together, these data show that cranial ⁵⁶Fe irradiation causes dose- and apoE isoform-dependent cognitive impairments in female mice and that anatomical specificity might contribute to the relative sensitivity of apoE4 mice to develop space radiation-induced cognitive impairments.