Individuals dramatically alter physiology and behavior to adapt to seasonal changes in their environment. To cope with winter stressors such as reduced food availability and low temperatures, central stress responses are presumably modulated at the level of the hypothalamic-pituitary-adrenal (HPA) axis, but the details remain unspecified. We examined the effects of long or short photoperiods (day lengths) on corticosterone responses to restraint, HPA negative feedback sensitivity, glucocorticoid receptor gene expression in the hippocampus, the role of corticosterone in spatial learning, and corticosterone responses to stressors associated with the spatial water maze task in adult male white-footed mice (Peromyscus leucopus). Short days increased corticosterone responses to restraint, increased hippocampal glucocorticoid receptor expression, enhanced corticosterone negative feedback on the HPA axis, and increased sensitivity to dexamethasone suppression of corticosterone. Although spatial learning and memory performance (via water maze) of all mice was impaired following pharmacological corticosterone inhibition, both water maze exposure and treatment injections alone were sufficient to increase short-day, but not long-day, corticosterone concentrations. Thus, the effects of corticosterone on spatial learning in these mice may be complicated by photoperiodic differences in stressor response to the learning task itself. Overall, these results suggest that photoperiod-evoked modification of the HPA axis and its potential behavioral consequences may be adaptive for winter survival.