Background: Letrozole is an aromatase inhibitor with conflicting studies reporting its effects on memory in male and female animals, and whether the observed memory impairments become exacerbated with an additional insult such as Alzheimer's disease (AD); an illness in which beta-amyloid and hyperphosphorylated Tau (p-Tau) protein accumulate. We examined Letrozole effects on memory, hippocampal p-Tau and histopathology in animals treated with Letrozole only or on top of induced AD, and investigated whether there would be any sex-based differences in memory status and/or p-Tau. Methods: 51 adult male and female Sprague Dawley rats were divided into: Control groups: Intact, Letrozole Vehicle, CSF, and CSF+Letrozole Vehicle, Letrozole group, Streptozotocin (STZ) group; with induced AD via cerebroventricular STZ injection in artificial CSF and, STZ+Letrozole (STZ-L) group. Memory was tested in a T-maze to measure alternation percentage. Hippocampal p-Tau protein levels were estimated using ELISA, and histopathology was documented in sections stained with Hematoxylin and Eosin. Results: There were significant reductions in alternation percentage in the STZ, Letrozole and STZ-L groups; most severe in the STZ-L group and least severe in the Letrozole group. Significant elevation in p-Tau concentration was observed in the STZ, Letrozole and STZ-L groups compared to the controls. No differences were found between males and females in all groups in any of the studied parameters. Histopathological examination showed neurodegeneration and inflammation in the Letrozole, STZ and STZ-L groups. Conclusion: Letrozole alters memory, more so in experimentally-induced AD, increases p-Tau and may cause hippocampal pathological changes, with no sex-based differences.