Decreased expression or function of UCP3 could reduce energy expenditure and increase the storage of energy. The aim of our study was to investigate the influence of -55CT polymorphism of the UCP3 gene on insulin concentrations and metabolic parameters secondary to two hypocaloric diets in obese patients. A population of 131 obese (body mass index >30), nondiabetic outpatients was analyzed in a prospective way. Before and after 2 months on two different hypocaloric diets, bipolar electrical bioimpedance, blood pressure measurement, serial assessment of nutritional intake with 3 d of written food records, and biochemical analysis were performed. The statistical analysis was performed based on a dominant model. With diet type I (low fat) and diet type II (low carbohydrate) in probands with both wild-type alleles, we observed decreases in BMI, weight, fat mass, systolic blood pressure, leptin levels, and insulin concentrations. In addition, with diet type II, a decrease in diastolic blood pressure, total cholesterol, and triglyceride levels was detected. Secondary to diet type I, a decrease in waist circumference and TNF-alpha was observed. Carriers of the T variant experienced decreases in BMI, weight, and fat mass on both diets, without statistical changes in biochemical parameters. In probands with both C alleles, both diets decreased insulin concentrations, blood pressure, and leptin concentrations. Weight reduction was similar with C and T alleles, independent of macronutrient distribution.