The uncoupling protein 3 (UCP3) gene has been suggested as a possible determinant affecting obesity risk given its function in the regulation of energy metabolism. However, available genetic association studies have been inconsistent, which could be attributable to not considering individual lifestyle patterns, such as physical activity, a factor that affects UCP3 expression. The objective of this study was to assess the association between the UCP3 -55C>T polymorphism and the risk of obesity.Case-control study conducted in a sample of Spanish adults. 157 obese subjects (BMI > or = 30) and 150 controls (BMI < 25) participated in the study. UCP3 -55C>T polymorphism was identified by the polymerase chain reaction-restriction fragment length polymorphism methodology.The odds ratio (OR) for obesity (95% confidence interval [CI]) according to the presence of UCP 3 gene -55C>T polymorphism (heterozygotes and homozygotes merged together), adjusting for age, sex, and recreational physical activity, was 0.61 (0.37-1.00), p = 0.05. Interestingly, this association was only manifest among those with higher recreational physical activity (OR: 0.46, 95% CI 0.21-0.99, p = 0.05) and not among those with lower physical activity (OR: 0.84, 95% CI 0.41-1.70, p = 0.84).UCP3 -55C>T polymorphism carriers have apparently a lower risk of obesity when taking into consideration recreational energy expenditure. Interestingly, this inverse beneficial association may only occur in people with a high level of physical activity.