Background and Aim: To evaluate the combined contribution of UCP3-55CT and PPARγ2 Pro12Ala polymorphisms as correlates of BMI, energy expenditure (REE) and substrate oxidation in people with type 2 diabetes., Methods and Results: Two independent population with type 2 diabetes were studied: population A, n = 272; population B, n = 269. Based on both UCP3 and PPARγ2 genotypes three groups were created. Carriers of the PPARγ2 Pro12Ala in combination with the CC genotype of UCP3 (ProAla/CC, group 1); carriers of only one of these genotypes (either CC/ProPro or CT-TT/ProAla, group 2); people with neither variants (CT-TT/ProPro, group 3). In both populations BMI (kg/m(2)) was highest in group 1, intermediate in group 2 and lowest in group 3, independent of energy intake (i.e 35.3 ± 6.7 vs 33.4 ± 5.4 vs 31.8 ± 3, p < 0.02, population A; 32.4 ± 4.2 vs 31.7 ± 3.8 vs 30.1 ± 2.7; p < 0.03, population B). People with the ProAla/CC genotype (group 1) showed similar REE, but lower lipid oxidation (10.9 vs 13.9 g/kg fat free mass/day; p = 0.04) and higher carbohydrate oxidation (23.6 vs 15.6 g/kg fat free mass/day; p = 0.02) than carriers of other genotypes., Conclusions: The combination of UCP3-55 CC and PPARγ2 Pro12Ala genotypes is associated with significantly higher BMI than other PPARγ2-UCP3 genotype combinations, partly due to a reduced ability in lipids oxidation. The relative importance of these mechanism(s) may be different in non diabetic people., (Copyright © 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)