Abnormal phosphorylation of tau protein is a common event in many neurodegenerative disorders, including Alzheimer's disease and other tauopathies. We investigated the relationship between hyperphosphorylated tau in brain extracts and mnemonic functions in rTg4510 mouse model of tauopathy. We report that rTg4510 mice showed rapid deterioration in spatial learning and memory, which paralleled a significant increase of hyperphosphorylated tau in the brain between 3 and 5.5 months of age. At 5.5 months, rTg4510 females showed significantly higher levels of hyperphosphorylated tau than males, with no evidence of differential tau transgene expression between the sexes. The increased levels of hyperphosphorylated tau in females were associated with more severe impairment in spatial learning and memory as compared to transgenic males. We also showed that within studied age range, the decrease in memory performance was accompanied by other behavioral disturbances in the water maze related to search strategy, like thigmotaxic swim and cue response. These findings suggest that the onset of abnormal tau biochemistry and coincident cognitive deficits in the rTg4510 mouse model is sex-dependent with females being affected earlier and more aggressively than males.