To date, our association study is the first to examine whether 141 tag SNPs in 8 TGF-β signaling pathway-associated genes, namely SMAD2, SMAD3, SMAD4, TGFB1, TGFB2, TGFB3, TGFBR1, and TGFBR2 genes, are significantly associated with the risk of MetS and its individual components independently, through gene–gene interactions, or both among Taiwanese individuals. Here, SMAD4 is linked to metabolic syndrome.