BACKGROUND & AIMS Interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α), two important inflammatory cytokines, have been inconsistently associated with risk of colon neoplasia in epidemiological studies. However, research to date has not adequately assessed whether race-specific differences may exist in associations between biomarkers and genetic variants of these cytokines and colorectal adenoma - the precursor lesions of colorectal cancer. We sought to determine whether circulating levels of IL-6 and TNF-α, or genetic polymorphisms in IL-6and TNF-α were associated with colon adenoma and if so, whether that association differed by race. METHODS We analyzed the associations of circulating levels and single nucleotide polymorphisms (SNPs) of IL-6 and TNF-α with risk of colon adenomas in a colonoscopy -based case-control study of 401 incident adenoma cases and 1,050 controls. We used multivariate unconditional logistic regression models to estimate the odds ratios (OR) and 95% confidence intervals (95% CI) for levels or genotypes (log additive models) of IL-6 and TNF-α. RESULTS Compared to the bottom tertile of IL-6, the adjusted ORs were: 1.06 (0.75-1.44), 1.01 (0.72-1.40), respectively for the 2(nd) and 3(rd) tertiles (ptrend = 0.10); the corresponding ORs for TNF-α were: 0.85 (0.63-1.15) and 1.01 (0.75-1.36), respectively (ptrend = 0.39). Race-stratified analyses did not reveal any significant association. There were also no statistically significant associations between IL-6 and TNF-α SNPs and colon adenoma. CONCLUSIONS Our results do not support pre-diagnostic levels of IL-6, TNF-α or their genetic variants as significant risk factors for the development of colon adenoma.