BACKGROUND & AIMS - Metabolic syndrome (MetS), characterized by abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, and insulin resistance is a major public health concern in the United States. The effect of Apolipoprotein E (Apo E) polymorphism has been relatively well studied in relation to cardiovascular disease; however, its effects on MetS are not well established. METHODS - We conducted a cross-sectional study consisting of 1,551 participants from the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study to assess the relation of Apo E polymorphism with the prevalence of MetS. Information on the different Apo E genotypes was extracted from the database and we defined MetS according to the AHA-NHLBI-IDF-WHO Harmonized Criteria. We used generalized estimating equations to estimate adjusted odds ratios for prevalent MetS and the Bonferroni correction to account for multiple testing in the secondary analysis. RESULTS – Our study population had a mean age (SD) of 56.5 (11.0) years and 49.7% had MetS. There was no association between the Apo E genotypes and MetS. The multivariable adjusted ORs (95% CI) were 1.00 (reference), 1.26 (0.31-5.21), 0.89 (0.62- 1.29), 1.13 (0.61-2.10), 1.13 (0.88-1.47) and 1.87 (0.91-3.85) for the *e3/e3, *e2/e2, *e2/e3, *e2/e4, *e3/e4 and *e4/e4 genotype respectively. In a secondary analysis, the *e2/e3 genotype was associated with lower HDL levels, with the multivariable adjusted ORs (95% CI) of 0.59 (0.36-0.95) when compared to the reference *e3/e3 genotype. CONCLUSIONS - Our findings do not support an association between Apo E polymorphism and MetS in a multi-center population based study of predominantly white US men and women. The *e2/e3 genotype was associated with lower HDL levels as compared to the *e3/e3 genotype. KEY WORDS: Apolipoprotein E (Apo E) polymorphism, metabolic syndrome, blood pressure, glucose, waist circumference, triglycerides, high-density lipoprotein cholesterol