The aim of this study was to investigate the effect of the microsomal triglyceride transfer protein (MTP) -493G/T polymorphism on clinical and biochemical parameters in relation to the presence of metabolic syndrome (MS). A group of 270 participants, 143 men and 127 women [50 men/36 women fulfilled the International Diabetes Federation (IDF) criteria of MS], was categorized on the basis of the MTP -493G/T polymorphism: GG homozygotes (Group GG) and carriers of the T allele (Group TT+TG). In men with MS, the presence of the T allele was associated with elevated concentrations of plasma insulin (by 48%, P<.01) and nonesterified fatty acids (by 49%, P<.05); homeostasis model assessment for insulin resistance index was higher by 64% (P<.05). Carriers of the T allele were further characterized by elevated plasma concentrations of total cholesterol (by 14%, P<.05) and by increased triglycerides in plasma (by 95%, P<.01) and in very low-density lipoprotein (by 106%, P<.01). They also had lower concentrations of n-6 polyunsaturated fatty acids in plasma phospholipids (by 3.5%, P<.05), lower Delta5-desaturase activities (by 18%, P<.05) and elevated concentrations of conjugated dienes in low-density lipoprotein (by 29%, P<.01). No significant differences between Groups GG and TT+TG were found in men without MS and in women with and without MS. Our results imply evidence for interactive effects of genetic, metabolic and gender-specific factors on several components of metabolic syndrome, which can increase the risk for cardiovascular disease.