The polymorphisms in the uncoupling protein 1 (UCP1, A to G) and beta3-adrenergic receptor (beta3-AR, Trp64Arg) genes have been suggested to be associated with an increased tendency to gain weight. We investigated the frequency of the A to G polymorphism of the UCP1 gene and its effect on basal metabolic rate (BMR) among obese Finns. We also examined the effects of the simultaneous occurrence of the polymorphisms in the UCP1 and beta3-AR genes on BMR. Altogether 170 obese subjects (29 men, 141 women, BMI 34.7beta3.8 kg/m2, age 43+/-8 years, mean+/-SD) participated in the study. The A to G substitution of the UCP1 gene was verified by digestion of the PCR product with Bcl I. The frequency of the A to G polymorphism of the UCP1 gene in obese subjects did not differ significantly from the population-based control subjects (5 vs 1 % for homozygotes (GG) and 35 vs 42 % for heterozygotes (AG), p=0.077, for trend). BMR adjusted for lean body mass, age and sex (adjBMR) was similar among the three UCP1 gene genotypes of obese subjects (AA n=90, AG n=72 or GG n=8). However, the subjects with the polymorphisms in both UCP1 and beta3-AR genes (n=18) had a 79 kcal/day (95% CI 30-128) lower adjBMR than the subjects without these polymorphisms (n=76) (1551+/-77 vs 1629+/-141 kcal/day, p=0.002). Furthermore, adjBMR was 63 kcal/day (95 % CI 7-118 kcal/day) lower in the subjects with both polymorphisms (n=18) compared with the subjects (n=14) who had only the polymorphism in the beta3-AR gene (1551+/-77 vs 1613+/-76 kcal/day, p=0.028). The A to G polymorphism of the UCP1 gene did not have an independent effect on BMR, but its simultaneous existence with the Trp64Arg polymorphism of the beta3-AR gene resulted in more lowered BMR than the Trp64Arg polymorphism of beta3-AR gene alone.