The prevalence of metabolic syndrome (MS) has been rising alarmingly worldwide, including in the United States, but knowledge on specific genetic determinants of MS is very limited. Therefore, we planned to identify the genetic determinants of MS as defined by National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATPIII) criteria. We performed linkage screen for MS using data from 692 Mexican Americans, who participated in the San Antonio Family Diabetes/Gallbladder Study (SAFDGS). We found strong evidence for linkage of MS on chromosome 7q (LOD = 3.6, empirical P = 6.0 × 10−5), between markers D7S2212 and D7S821. In addition, six chromosomal regions exhibited potential evidence for linkage (LOD ≥ 1.2) with MS. Further, we examined 29 single nucleotide polymorphisms (SNPs) from the fatty acid translocase (FAT or CD36, 18 SNPs) gene and guanine nucleotide binding protein, alpha transducing 3 (GNAT3, 11 SNPs) gene, located within the 1-LOD support interval region for their association with MS and its related traits. Several SNPs were associated with MS and its related traits. Remarkably, rs11760281 in GNAT3 and rs1194197 near CD36 exhibited the strongest associations with MS (P = 0.0003, relative risk [RR] = 1.6 and P = 0.004, RR = 1.7 respectively) and several other related traits. These two variants explained about 18% of the MS linkage evidence on chromosome 7q21, and together conferred approximately 3-fold increase in MS risk (RR = 2.7). In conclusion, our linkage and subsequent association studies implicate a region on chromosome 7q21 to influence MS in Mexican Americans.