AIMS: The aim of our study was to investigate the influence of -55CT polymorphism of UCP3 gene on metabolic response, weight loss and serum adipokine levels to a high monounsaturated fat hypocaloric diet in obese patients. PATIENTS AND METHODS: A sample of 128 obese patients was analyzed in a prospective way during 3 months. RESULTS: Eighty eight patients (21 males/67 females) (68.8%) had the genotype 55CC (wild genotype group) and 40 patients (8 males/32 females) (31.3%) 55CT (mutant genotype group). In wild genotype group, BMI (-1.6 +/- 1.3 kg/m(2)), weight (-4.3 +/- 3.7 kg), fat mass (-3.5 +/- 3.3 kg), waist circumference (-5.1 +/- 2.9 cm), total cholesterol (-7.2 +/- 10.6 mg/dl), LDL cholesterol (5.3 +/- 12.8 mg/dl) and leptin (-4.+/- 10.1 ng/ml) decreased. In mutant genotype group, BMI (1.3 +/- 2.2 kg/m(2)), weight (-3.0 +/- 1.4 kg), fat mass (-2.5 +/- 1.1 kg), waist circumference (-2.8 +/- 3.1 cm) and leptin (-5.8 +/- 10.7 decreased. CONCLUSIONS: In patients with -55CC UCP3 genotype, a high mono-unsaturated hypocaloric diet reduced BMI, weight, waist circumference, waist to hip ratio, fat mass, LDL-cholesterol, total cholesterol and leptin levels. Carriers of T allele had a different response than -55CC patients, with a significant decrease of the same antropometric parameters, but lower than in the wild genotype group, and without significant changes in cholesterol levels.