Tumor necrosis factor-alpha (TNF-alpha) is expressed primarily in adipocytes, and elevated levels of this cytokine have been linked to obesity and insulin resistance. The purpose of this investigation was to test whether the TNF-alpha-308 polymorphism (previously linked to insulin resistance and increased leptin levels) and the TNF-alpha-238 polymorphism (linked to decreased insulin resistance) were associated with insulin resistance or obesity-related traits in 424 subjects self-referred to the Johns Hopkins Weight Management Center (JHWMC). There were no differences in allele frequencies of either polymorphism by obesity category in the JHWMC and a lean control group. Despite previous smaller studies that have linked insulin resistance and the 308 allele, we found no such relationship in the JHWMC population. Instead, homozygotes for this allele had a significantly lower BMI than their counterparts without the polymorphism. In addition, we found no relationship between the 238 polymorphism and BMI, fasting glucose, or log of fasting insulin.