Metabolic syndrome (MetS) is a combination of medical disorders, consisting of multiple, interrelated risk factors of metabolic origin. To investigate the associations of MetS with appetite-related genes (LEPR, near MC4R and SH2B1) and cholesterol metabolism-related gene (LRP5) polymorphism variants and the joint effect of cigarette smoking and these polymorphism variants on MetS in a community-based case-control study. Metabolic syndrome was defined according to the American Heart Association and National Heart Lung Blood Institute (AHA/NHLBI) criteria. A total of 237 MetS cases and 202 subjects without MetS aged 40 or over in Taiwan were analyzed. The genotypes of LRP5-rs3736228, LEPR-rs1137100, near MC4R-rs17782313 and SH2B1-rs4788102 were analyzed by the PCR-restriction fragment length polymorphism method. A strong association of the SNP rs17782313 near MC4R gene with MetS susceptibility was found. The data indicated that the C allele of near MC4R-rs17782313 is an obvious risk factor for MetS susceptibility. The joint effects of cigarette smoking and susceptible genotypes of LRP5, LEPR, near MC4R or SH2B1 genes led to a relatively higher risk of having MetS. Using subjects with the wild-type of LRP5, LEPR, near MC4R or SH2B1 genes and without a smoking habit as a reference group, those with cigarette smoking (current and former) and more than one variant type had a 4.1-fold (95 % CI = 1.6-10.2) risk of having MetS. The genotypes of the appetite-related genes (LEPR, near MC4R and SH2B1) and cholesterol metabolism-related gene (LRP5), together with a cigarette smoking habit, are important risk factors for MetS.