Apolipoprotein E (apoE) is associated with familial and sporadic Alzheimer's disease (AD). Stress has been identified as a putative risk factor of AD. Thus, in the present study we examined the susceptibility of apoE-deficient mice to stress. The results obtained revealed that the elevation of corticosterone levels in apoE-deficient mice following restraint stress is markedly lower than in controls, and that these mice differ in their behavioral pain response to noxious stimuli in both stress and non-stress conditions. These findings suggest an interplay between apoE and the response to stressful stimuli and provide a model for elucidating the relationship between apoE and susceptibility to stress.