This study tests the hypothesis that a history of common stressful experiences further promotes the cognitive deficit of apolipoprotein E (apoE)-knockout mice, an animal model to study aspects of Alzheimer's disease. In experiment 1, apoE-knockout and wild-type mice were repeatedly subjected to an environmental challenge (i.e. exposure to rats) and the effect was monitored on Morris water maze performance. Naive apoE-knockout mice were impaired, but surprisingly after rat stress their water maze performance improved and switched to a goal-directed search strategy. Rat stress induced in wild-type mice spatial learning deficits and an inefficient search strategy. Swim ability was not affected by rat stress and under basal conditions measures for locomotion and anxiety were similar for both genotypes. In experiments 2 and 3, we found that the rat stress paradigm attenuated the elevation of basal and stress-induced corticosterone concentrations in the apoE-knockout mice towards concentrations observed in wild-type mice. The expression of hippocampal mineralocorticoid and glucocorticoid receptor mRNA was similar in both genotypes, but in response to rat stress, the level of glucocorticoid receptor mRNA increased selectively in the CA1 pyramidal field. In conclusion, repeated exposure to a common environmental experience did abolish and reverse the difference in cognitive performance and corticosterone concentrations of apoE-knockout and wild-type mice.