Objective: To investigate the relationship between MKKS gene variations, obesity-related traits and features of the metabolic syndrome (MS) in the Greek population. Design and subjects: Genotype and haplotype analysis was carried out for six known MKKS gene polymorphisms (534C4T, 985 þ 16T4G, 985 þ 33C4G, 986À29A4T, 1161 þ 58A4G and 1595G4T) in 220 obese subjects (body mass index X30 kg/m 2 ) and 330 non-obese controls. Results: Genotype frequencies of the 985 þ 16T4G, 986À29A4T and 1595G4T SNPs were significantly different between obese and non-obese individuals (P ¼ 0.0016, 0.0196 and 0.0069, respectively). Obese carriers of the risk alleles of the above three polymorphisms had a significantly increased prevalence of arterial hypertension. Furthermore, obese carriers of the G allele for the 985 þ 16T4G polymorphism had an increased prevalence of type 2 diabetes mellitus and of MS component traits. A new polymorphism was detected, namely a C to T substitution at position 1129 (1129C4T or N377N). Frequency of the T allele for the 1129C4T polymorphism was significantly higher in control individuals than in obese subjects (P ¼ 0.0253). Haplotype TGTGT was more prevalent in obese than in controls (P ¼ 0.0002) and was associated with increased prevalence of the MS in obese subjects (Po0.0001). Conclusion: Our results suggest that genetic variation in the MKKS gene may play a role in the development of obesity and the metabolic syndrome.