Background and Purpose-Psychosocial stress has been widely studied as a risk factor for stroke and coronary heart disease (CHD) but little is known about the differential effects of stress on stroke and CHD risk by race and sex. Caregiving for a disabled spouse has been associated with increased mortality and CHD risk, but the association of caregiving strain with stroke and CHD risk across race and sex is unknown. Methods-Participants in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study who were providing in-home caregiving to a disabled spouse reported on caregiving strain (high, some, or none), depressive symptoms, social network, education, and age. Caregiving strain groups were compared on the Framingham Stroke Risk Score (N=716) and Framingham CHD Risk Score (N=607), which estimate the projected 10-year risk of incident stroke and ischemic heart disease, respectively. Results-High caregiving strain was associated with a 23% higher covariate-adjusted estimated stroke risk (11.06% for caregivers with no strain versus 13.62% risk for high-strain caregivers). This association was stronger in men, particularly African American men with high caregiving strain (26.95% estimated 10-year stroke risk). Caregiving strain was not associated with CHD risk scores. Conclusions-Caregiving strain is significantly associated with higher estimated stroke risk with greatest effects for men, particularly African American men, providing caregiving to their wives. Male spouse caregivers may need special caregiving support. Prospective longitudinal studies should examine how sex and race may moderate the impact of stress on stroke and CHD risk. Copyright © 2010 American Heart Association. All rights reserved.