Few studies have assessed the effect of the NPY gene rs16147 variant on metabolic response following a dietary intervention. We evaluated the effect of rs16147 on body weight and biochemical changes after a high-protein/low-carbohydrate hypocaloric diet compared with a standard severe hypocaloric diet over 9 months.A population of 270 obese individuals was enrolled. At baseline, participants were randomly allocated to one of two hypocaloric diets, high protein (Diet HP) or standard (Diet S), for a period of 9 months.After both diets, all genotypes showed decreased body mass index, weight, fat mass, waist circumference, and leptin levels. Participants with the minor allele (A) assigned to the HP diet showed decreases in total cholesterol (-6.5 ± 4.8 vs 10.1 ± 4.1 mg/dL; p < 0.05), LDL cholesterol (-5.9 ± 3.8 vs 9.6 ± 2.4 mg/dL; p < 0.05), triglycerides (-1.0 ± 4.8 vs 16.2 ± 4.1 mg/dL; p < 0.05), insulin (-0.5 ± 2.8 vs 1.7 ± 2.1 UI/L; p < 0.05), HOMA-IR (-0.2 ± 2.1 vs 0.5 ± 2.0 units; p < 0.05), and CRP (-0.3 ± 0.4 vs 1.3 ± 0.2 mg/dL; p < 0.05). Participants with the minor allele assigned to diet S also showed decreases in total cholesterol (-6.1 ± 4.1 vs 14.4 ± 3.1 mg/dL; p < 0.05), LDL-cholesterol (-3.1 ± 2.8 vs 15.0 ± 3.1 mg/dL; p < 0.05), triglycerides (-6.9 ± 4.1 vs 13.2 ± 4.0 mg/dL; p < 0.05), insulin (-0.3 ± 2.1 vs. -1.2 ± 0.2 UI/L: p < 0.05), HOMA-IR (-0.3 ± 2.1 vs. -1.6 ± 1.1 units: p < 0.05), and CRP (-0.4 ± 0.1 vs 1.1 ± 0.2 mg/dL; p < 0.05).In obese Caucasians, the presence of the A allele of the rs16147 genetic variant produces a better metabolic response that is secondary to weight loss with two different hypocaloric diets.