Tumor necrosis factor alpha (TNF-alpha) is a multifunctional cytokine constitutively produced by adipose tissue that may mediate insulin resistance. Studies in Caucasian subjects have suggested that the G-308A transition in the 5' region of the TNF-alpha gene may be associated with insulin resistance and obesity. These factors have been proposed to underlie the clustering of type 2 diabetes, hypertension, and dyslipidemia found in the metabolic syndrome, the prevalence of which is reaching epidemic proportions in Hong Kong Chinese. We investigated the association of this gene polymorphism with the components of the metabolic syndrome including the lipid profile, as well as with the indices of obesity and insulin resistance as measured by the insulin-glucose product, in 440 Chinese subjects (healthy [27.5%] and overlapping groups with type 2 diabetes [54.1%], hypertension [38.8%], dyslipidemia [39.3%], or obesity [39.5%]). The frequency of the mutant A allele was 7.4% in 121 healthy controls and 9.0% in the total population. The mutation was not associated with any component of the metabolic syndrome or with the prevalence of albuminuria and retinopathy in these subjects. Furthermore, there was no difference in anthropometric measures, insulin resistance, or lipid levels between subjects with the GG genotype and those with the mutant allele. In summary, the TNF-alpha gene G-308A polymorphism is unlikely to play an important role in the development of these disorders in this population.