The role of ADIPOQ gene rs266729 variants on weight loss after a dietary intervention are still unclear. To analyze the effects of the ADIPOQ gene rs266729 variant n weight loss, cardiovascular risk factors, and adiponectin levels after two hypocaloric diets with different dietary fatty profiles. A population of 362 obese patients was enrolled in a randomized clinical trial with two diets (Diet M, monounsaturated fat-enriched diet, and Diet P, polyunsaturated-fat enriched diet). Anthropometric measurements, an assessment of nutritional intake, and biochemical tests were performed at baseline and after 12 weeks. Weight loss was similar with both diets. After Diet M, only subjects with CC genotype showed significant improvements in total cholesterol (CC vs. CG±GG) (-9.0±1.1mU/L vs. -4.5±2.4mg/dL, p=0.01), LDL cholesterol (-6.0±1.1mg/dL vs. -3.0±0.9mg/dL, p=0.03), glucose (-4.7±1.1mg/dL vs. -0.6±0.5mg/dL, p=0.01), and insulin levels (-2.6±1.0mU/L vs. -0.7±0.3mU/L, p=0.02) and in HOMA-IR (-0.5±0.2 units vs. -0.2±0.4 units, p=0.03). The same improvement was reported after Diet P in all parameters, including total cholesterol (CC vs. CG±GG) (-8.0±1.2mU/L vs. -2.1±1.4mg/dL, p=0.02), LDL cholesterol (-7.3±1.2mg/dL vs. -2.1±0.8mg/dL, p=0.02), glucose (-3.2±0.1mg/dL vs. -0.2±0.5mg/dL, p=0.01), and insulin levels (-2.5±1.0mU/L vs. -1±0.6mU/L, p=0.02) and HOMA-IR (-0.5±0.1 units vs. -0.3±0.4 units, p=0.02). Only subjects with CC genotype showed significant increases in adiponectin levels after both diets: (Diet M: 10.3±2.0ng/dL vs. Diet P: 9.3±2.9ng/dL, p=0.43). The CC genotype of ADIPOQ gene rs266729 variant is associated to increased adiponectin levels and decreases in LDL cholesterol, glucose, insulin, and HOMA-IR levels after weight loss. Copyright © 2019 SEEN y SED. Publicado por Elsevier España, S.L.U. All rights reserved.