BACKGROUND: Different fatty acids may vary in their effect on the metabolic syndrome (MetS). We tested whether fatty acid classes measured in erythrocytes are associated with the MetS or its components. METHODS: Included were men [n = 497; mean (SD) age, 49 (16) years] and women [n = 539; age, 48 (16) years] from 187 families in a National Heart, Lung, and Blood Institute (NHLBI) family study of the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) conducted in Utah and Minnesota. We used gas chromatography to measure erythrocyte fatty acids and obtained data on potential confounding variables from interviewer-administered questionnaires. RESULTS: The prevalence of the MetS as defined by the updated Adult Treatment Panel III criteria was 36.8% in Utah and 39.6% in Minnesota (P >0.05). In a multivariate model that included 4 fatty acid classes, covariates, and pedigree as a random effect, the odds ratios (95% confidence interval) for the MetS in the 1st, 2nd, 3rd, and 4th quartile of polyunsaturated fatty acids were 1.00, 0.72 (0.47-1.10), 0.67 (0.43-1.05), and 0.39 (0.24-0.64), respectively (P for trend = 0.0002). For the corresponding quartiles of saturated fatty acids, the odds ratios were 1.00, 1.19 (0.77-1.84), 1.48 (0.94-2.34), and 1.63 (1.01-2.63), respectively (P for trend = 0.03). Unlike n6 fatty acids, which showed an inverse association (P<0.05) with MetS, n3, trans, and monounsaturated fatty acids were not associated with the MetS (P >0.05). We observed significant correlations (P<0.05) between fatty acid classes, insulin, and components of the MetS. CONCLUSIONS: Polyunsaturated fats are inversely associated with the MetS, whereas saturated fatty acids are positively associated with the MetS, probably through their effect on lipids, adiposity, insulin, and blood pressure.