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Obesity is one of modifiable risk factors for clear cell renal cell cancer (ccRCC). We aim to identify the association between obesity-driven biomarkers and ccRCC risk. This is a retrospective, two-phase, case-control study involving 682 cases and 733 controls. Obesity-driven biomarkers [gastric inhibitory polypeptide (GIP), C-peptide, insulin, resistin, adipsin, peptide YY, pancreatic polypeptide, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), plasminogen activator inhibitor-1, monocyte chemoattractant protein 1, lipocalin2, leptin, adiponectin] were measured using the Milliplex method. Multivariate logistic regression was used to assess the associations between biomarkers and ccRCC risk. Results revealed that GIP, C-peptide, IL-6 and TNF-α levels were consistently distinct between cases and controls. These markers were significantly associated with ccRCC risk in both phases (except C-peptide). In the combined population, compared with individuals with low levels of the biomarkers, individuals with high level of GIP [odds ratio (OR) = 0.52, 95% confidence interval (CI): 0.40-0.67] had lower risk, whereas individuals with high levels of C-peptide (OR = 1.46, 95% CI: 1.15-1.87), IL-6 (OR = 2.20, 95% CI: 1.50-3.22), TNF-α (OR = 1.90, 95% CI: 1.49-2.43) had significantly higher risk. Stratified analysis showed consistent associations with ccRCC risk in most subgroups (P < 0.05). The risk score based on the IL-6, TNF-α and GIP was positively associated with ccRCC risk in a dose-response manner (P for trend = 2.18E-13). Data from The Cancer Genome Atlas indicate that insulin signaling, IL-6 signaling and TNF-α signaling were enhanced in tumors. Collectively, our study demonstrates the integrative effect of insulin resistance and inflammation in ccRCC development, which may elucidate the basis of association between obesity and carcinogenesis. Further confirmation in prospective cohort studies are warranted for clinical applications in prevention and precision medicine of ccRCC.