BACKGROUND: Inflammation is implicated in causing diabetes. We tested whether transcription factor 7 like-2 (TCF7L2) gene polymorphisms (rs12255372 and rs7903146), consistently associated with type 2 diabetes, are associated with plasma concentrations of inflammatory markers before and after three weeks of daily treatment with fenofibrate. METHODS: Men and women in the Genetics of Lipid-Lowering Drugs and Diet Network study (n = 1025, age 49 +/- 16 y) were included. All participants suspended use of lipid-lowering drugs for three weeks and were then given 160 mg/day of fenofibrate for three weeks. Inflammatory markers and lipids were measured before and after fenofibrate. ANOVA was used to test for differences across TCF7L2 genotypes. RESULTS: Under the additive or dominant model, there were no significant differences (P > 0.05) in the concentrations of inflammatory markers (hsCRP, IL-2, IL-6, TNF-alpha and MCP-1) across TCF7L2 genotypes in the period before or after treatment. For both rs12255372 and rs7903146, homozygote T-allele carriers had significantly higher (P < 0.05) post-fenofibrate concentrations of MCP-1 in the recessive model. No other significant associations were detected. CONCLUSION: Overall these data show no association between TCF7L2 polymorphisms and the inflammatory markers suggesting that the effects of TCF7L2 on diabetes may not be via inflammation.