The authors examined relationships between chronic stress and cognitive decline and whether such relationships were mediated by psychophysiological factors. Ninety-six caregivers of spouses with Alzheimer's disease (AD) were compared with 95 similar noncaregiver spouses. All were free of diabetes. Although the groups started similarly, over 2 years caregivers declined by a small but significant amount (1 raw score point and 4 percentile points, each p<.05) on Shipley Vocabulary. In contrast, noncaregivers did not change. Higher hostile attribution (beta=-.09; p<.05) and metabolic risk (beta=-.10; p<.05) in caregivers mediated the cognitive decline. This is the first study of cognitive decline and mediators in caregivers. This work has implications for caregiver and care-recipient health and for research on cognition, psychophysiology, diabetes, and AD.