Background Adiposity increases endometrial cancer (EC) risk, possibly through inflammation, hyperinsulinemia, and increasing estrogens. We aimed to quantify the mediating effects of adiponectin (anti-inflammatory adipocytokine); interleukin-6, interleukin-1-receptor antagonist, TNF-receptor-1 and -2, and C-reactive protein (inflammatory status biomarkers); C-peptide (hyperinsulinemia biomarker); free estradiol and estrone (estrogen biomarkers) in the adiposity-EC link in postmenopausal women. Methods We used data from a case-control study within the European Prospective Investigation into Cancer and Nutrition. Eligible women had not had cancer, hysterectomy, diabetes, did not use oral contraceptives or hormone therapy, and were postmenopausal at recruitment. Mediating pathways from adiposity to EC were investigated by estimating natural indirect (NIE) and direct (NDE) effects using sequential mediation analysis. Results The study included 163 cases and 306 controls. The adjusted odds ratio (OR) for EC for BMI≥30vs.18.5≤BMI<25kg/m2 was 2.51 (95%CI 1.26-5.02). The ORsNIE were 1.95 (1.01-3.74) through all biomarkers (72% proportion mediated (PM)) decomposed as: 1.35 (1.06-1.73) through pathways originating with adiponectin (33%PM); 1.13 (0.71-1.80) through inflammation beyond [the potential influence of] adiponectin (13%PM); 1.05 (0.88-1.24) through C-peptide beyond adiponectin and inflammation (5%PM); and 1.22 (0.89-1.67) through estrogens beyond preceding biomarkers (21%PM). The ORNDE not through biomarkers was 1.29 (0.54-3.09). Waist circumference gave similar results. Conclusion Reduced adiponectin and increased inflammatory biomarkers, C-peptide, and estrogens mediated ~70% of increased odds of EC in women with obesity vs. normal weight. Impact If replicated, these results could have implications for identifying targets for intervention to reduce EC risk in women with obesity.