OBJECTIVE: Some adiponectin gene (ADIPOQ) single-nucleotide polymorphisms (SNPs) have been related to basal and adiponectin levels and metabolic parameters. The aim of this study was to evaluate the effect of the genetic variant rs1501299 ADIPOQ gene on biochemical changes after weight loss secondary to a high-protein and low-carbohydrate diet versus a standard severe hypocaloric diet over 9 mo as the primary endpoint. METHODS: A white population of 270 obese patients was enrolled in a randomized clinical trial with two hypocaloric diets (high-protein and low carbohydrate diet [HP] versus standard diet [S]) over 9 mo of intervention. The statistical analysis was performed for the combined GT and TT as a group (T-allele carriers) and GG as second group (non-T-allele carriers). Before and after 12 wk on each hypocaloric diet, an anthropometric evaluation, an assessment of nutritional intake, and a biochemical analysis were realized. RESULTS: With both dietary interventions, body weight, body mass index (BMI), fat mass, waist circumference, systolic blood pressure, and leptin levels decreased. In non-T-allele carriers after both diets, the decrease in total cholesterol levels -12.3 ± 2.2 mg/dL (T-allele carriers -6.9 ± 2.1 mg/dL; P = 0.01 diet HP) and 12.2 ± 3.1 mg/dL (T-allele carriers -4.7 ± 1.2 mg/dL; P = 0.02 after diet S), low-density lipoprotein cholesterol -13.2 ± 2.7 mg/dL (T-allele carriers -6.1 ± 2.1 mg/dL; P = 0.02 after diet HP) and -9.3 ± 1.8 mg/dL (T-allele carriers -4.8 ± 2.9 mg/dL; P = 0.01 after diet S), triacylglycerol levels -12.7 ± 6.1 mg/dL (T-allele carriers -6 ± 2.9 mg/dL; P = 0.01 after diet HP) and -16.3 ± 7.2 mg/dL (T-allele carriers -5.3 ± 1.4 mg/dL; P = 0.03 after diet S), insulin levels -5 ± 1.1 mUI/L (in T-allele -1.7 ± 0.9 mUI/L; P = 0.02 after diet HP) and -3.2 1.1 mUI/L (T-allele carriers -0.7 ± 0.7 mUI/L; P = 0.02 after diet S), and homeostatic model assessment of insulin resistance levels -0.4 ± 0.2 units (T-allele group -0.1 ± 0.1; P = 0.04 after diet HP) and -0.7 ± 0.1 units (T-allele carriers -0.1 ± 0.5 mg/dL; P = 0.01 after diet S) was higher than T-allele carriers. Only no T-allele carriers showed an increase in adiponectin levels after both diets. CONCLUSION: After two different hypocaloric diets during 9 mo of intervention, the GG genotype of an ADIPOQ gene variant (rs1501299) is related to better improvement in adiponectin levels, insulin resistance, and lipid profile than T-allele carriers.