Several genetic factors have been investigated responsible for metabolic syndrome (MetS). The aim of this study was to investigate the association between cholesteryl ester transfer protein (CETP) TaqIB and apolipoprotein E (ApoE) polymorphisms and MetS in 378 subjects from Southern Thailand. Subjects were divided into MetS+ (n = 121) and MetS- (n = 257) groups according to the criteria of National Cholesterol Education Program Adult Treatment Panel III (NCEP ATPIII). The CETP TaqIB and ApoE polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. Logistic regression analysis revealed no association of CETP TaqIB and ApoE variants with MetS, after adjustment for age and sex. However, ε4 allele had a significantly increased odds ratio (OR) of reduced high-density lipoprotein-cholesterol (HDL-C) levels when compared with ε3 allele (OR 1.91; 95% CI 1.11-3.29, p = 0.020). This suggests that CETP TaqIB and ApoE polymorphisms may not be considered as genetic risk factors for MetS in a Southern Thai population. However, ε4 allele which is associated with one metabolic component, low HDL-C levels, might predispose the subjects to develop metabolic disturbances.