Prospective studies have reported a positive association of excess fatigue and hopelessness with coronary heart disease mortality; a relation to atherosclerosis has not been investigated. We examined the cross-sectional association of the Maastricht excess fatigue questionnaire with carotid intimal-medial wall thickness among 12,448 coronary heart disease-free individuals age 47-68 years. In age-, race-, and field center-adjusted analyses, we found a strong, positive association between excess fatigue and carotid intimal-medial wall thickness in both sexes. Adjustment for other coronary heart disease risk factors substantially attenuated the relation. Pack-years of smoking was the strongest confounder. Furthermore, there was little association among never-smokers. It appears that the association of excess fatigue with atherosclerotic disease is largely accounted for by established risk factors.