We examined the relation of fatty acid composition of plasma phospholipids and cholesterol esters with carotid artery intima-media thickness (a measure of atherosclerosis) in 2872 white men and women aged 45-64 y from the Minneapolis center of the Atherosclerosis Risk in Communities Study. In both men and women, average carotid intima-media thickness was associated significantly (P < 0.01) and positively with saturated (SFA) and monounsaturated fatty acid composition, and inversely with polyunsaturated fatty acid (PUFA) composition and the ratio of PUFAs to SFAs in both phospholipids and cholesterol esters. These associations were independent of age, cigarette smoking, low-density-lipoprotein (LDL) cholesterol, high-density-lipoprotein (HDL) cholesterol, body mass index, diabetes, and hypertension in men; but in women, only SFAs and PUFAs in the cholesterol esters and the ratio of PUFAs to SFAs were independently associated. The plasma fatty acid pattern is associated with carotid atherosclerosis in a direction generally consistent with the dietary fat-coronary artery disease relation. These results support recommendations to reduce dietary saturated fat to prevent cardiovascular disease.