The study systematically evaluated obesity-related risk factors as potential mediators in the origin of kidney cancer using longitudinal cohort analyzes and Mendelian randomization. Cohort analyzes were conducted in the UK Biobank (472,337 participants, 1,382 kidney cancer cases over 5,586,414 person-years) and the Swedish VIP study (204 couples). Mendelian randomization used a GWAS with 27,213 cases and 486,846 controls. They found consistent positive associations with kidney cancer risk for fasting insulin (ORMR 2.24, 95% CI 1.19-4.22; HRcohort 1.43, p=0.04), triglycerides (ORMR 1.11, 95% CI 1.05-1.17; HRcohort 1.23, 95% CI 1.11-1.38), diastolic blood pressure (ORMR 1.09, 95% CI 1.04-1.26; HRcohort 1.11, 95% CI 1.05-1.17). Consistent inverse associations were for SHBG (ORMR 0.80, 95% CI 0.70-0.92; HRcohort 0.67, 95% CI 0.58-0.76) and HDL cholesterol (ORMR 0.93, 95% CI 0.88-0.98; HRcohort 0.66, 95% CI 0.59-0.77). The study highlights the roles of these factors in mediating the relationship between obesity and kidney cancer risk, with limitations in statistical power for some factors.