This cross-sectional study investigates the association of hostility and social support (measured by standardized instruments) to carotid artery atherosclerosis in men and women with a high familial risk for coronary heart disease (CHD) and those with low to medium risk. The hypothesis was that high hostility and low social support would have a stronger association in subjects with a familial predisposition to CHD. There were 535 low- to medium-risk women, 491 low- to medium-risk men, 1,950 high-risk women, and 1,667 high-risk men in the study. The extent of carotid artery atherosclerosis was assessed by B-mode ultrasound imaging. A lesion was defined as an intimal-medial far wall thickness of 1 mm in the common, internal, or carotid bifurcation, or identification of plaque at any site. Odds ratios and their 95% confidence intervals were calculated using generalized estimating equations (GEE) for logistic regression. Family was specified as the clustering variable, and robust SEEs were obtained that account for dependence of the data within families. After controlling for age, education, body mass index, ever having smoked, ever drinking > 5 drinks a day, and metabolic index, hostility was significantly associated with increased odds of carotid lesions in only high-risk women. High-risk women showed a significantly reduced odds of carotid lesions with high social support, but the extent of this protection was reduced when age and education were included in the equation. A combination of high hostility and low social support was associated with higher odds than hostility alone in both high-risk men and women. These results suggest that women with a high familial predisposition for CHD may be more vulnerable to cardiovascular influences from hostility and social support than high-risk men or men and women with low to medium risk.