The objective of this study is to examine how chronic stress in major life domains [relationship, work, sympathetic-caregiving, financial] relates to CVD risk, operationalized using the inflammatory marker C-Reactive Protein (CRP), and whether gender differences exist. Participants were 6,583 individuals aged 45-84 years, recruited as part of the Multi-Ethnic Study of Atherosclerosis. Demographic and behavioral factors, health history, and chronic stress were self-reported. CRP was obtained through venous blood draw. In aggregate, gender by chronic stress interaction effects accounted for a significant, albeit small, amount of variance in CRP (P < .01). The sympathetic-caregiving stress by gender interaction was significant (P < .01); the work stress by gender effect approached significance (P = .05). Women with sympathetic-caregiving stress had higher CRP than those without, whereas no difference in CRP by stress group was observed for men. Findings underscore the importance of considering gender as an effect modifier in analyses of stress-CVD risk relationships.