Few epidemiologic studies have examined the association between an overall fatty acid (FA) profile and coronary heart disease (CHD) risk. To examine a novel index that summarizes individual FA levels based on FA affinity and fluidity in relation to CHD risk in men. In a prospective nested case-control study, FAs in plasma and erythrocytes were measured in 459 CHD cases and 879 matched controls. Lipophilic index (LI) was computed by summing the products between FA levels and melting point of each FA to reflect the overall FA lipophilicity. Among controls, higher plasma LI was significantly correlated with adverse profiles of blood lipids, inflammatory markers, and adiponectin. After multivariate adjustment for age, smoking, body mass index, and other CHD risk factors, plasma LI was significantly associated with an increased risk of CHD: the relative risk was 1.61 (95% confidence interval: 1.03, 2.53; P for trend=0.04) comparing extreme quintiles. This association was attenuated to 1.21 (0.48, 3.09; P for trend = 0.77) after adjusting for plasma levels of total trans FAs, long-chain n-3 FAs, and polyunsaturated to saturated fat ratio. Erythrocyte LI was not significantly associated with CHD risk. Our data indicate that a novel lipophilic index is associated with an adverse profile of cardiovascular risk markers and increased risk of CHD in men, its usefulness as a complement of individual fatty acids in assessing disease risk needs to be elucidated in future studies.