Mice deficient in apoE (Apoe-/-) can be used to assess the potential role of apoE in the effects of cranial irradiation on hippocampal function. Radiation-induced impairments in hippocampal function may be more pronounced in female Apoe-/- mice and more pronounced in mice irradiated and tested cognitively later in life. To assess this possibility, female wild-type and Apoe-/- mice were irradiated at 6 months of age with 10 Gy 137Cs gamma rays and tested cognitively 3 months later. Sham-irradiated wild-type female mice showed enhanced hippocampal-dependent novel location recognition compared to sham-irradiated Apoe-/- female mice. However, cranial irradiation impaired novel location recognition similarly in both genotypes. Cranial irradiation also impaired hippocampal-dependent spatial memory retention similarly in wild-type and Apoe-/- female mice in the water maze. Because novel location recognition was not affected after 137Cs gamma irradiation in younger mice, these data support the possibility that older mice are more susceptible to the effects of gamma radiation on novel location recognition. Together with the impairments in spatial memory retention in the water maze after irradiation, these data support the existence of detrimental effects of cranial irradiation on hippocampal function. In addition, compared to wild-type female mice, Apoe-/- female mice showed enhanced levels of anxiety, and in Apoe-/-, but not in wild-type, female mice, radiation decreased levels of anxiety. Because levels of anxiety during the hidden session of the water maze were associated with ability to locate the hidden platform, assessments of anxiety need to be considered in evaluating the effects of cranial irradiation on cognitive performance after cranial irradiation.