The prevalence of cardiovascular risk factors, especially low level of high density lipoprotein cholesterol (HDL-C), is very high in Iran. The associations of apolipoprotein E (Apo E) polymorphism with lipid profile, especially high density lipoprotein (HDL) subfractions, were examined in Iranian population. A cross-sectional study of 1030 subjects (452 men and 578 women) from the Tehran Lipid and Glucose Study (TLGS) was performed. Serum triacylglycerol, cholesterol, FBS, HDL-C levels and its subfractions, Apo B and Apo A1 were determined and body mass index and blood pressure were measured. A segment of the mentioned gene was amplified by PCR and the polymorphisms were revealed by RFLP using HhaI restriction enzyme. Allele frequencies obtained for APOE Ã 2, APOE Ã 3, and APOE Ã 4 were 5.77, 85.92, and 8.3%, respectively. The presence of the e2 allele was significantly associated with increased serum HDL-C levels and its subfractions both in men and women except HDL3 in men. The LDL/HDL ratio was significantly lower in female. The relations were significant even after adjustment for age, sex, and BMI but hypertension, smoking, and diabetes status decreased the effect of Apo E2 on HDL-C and HDL subfractions. The observed genotype and allele frequencies were similar to those reported for other Caucasians samples. Apo E2 increased the level of HDL-C, HDL subfractions, and decreased the LDL/HDL ratio. These findings highlight the important effect of variation in this gene on lipid levels.