OBJECTIVE: Thyroid hormone receptor-beta resistance has been associated with metabolic traits. THRA gene sequencing of an obese woman (index case) who presented as empirical thyroid hormone receptor-α (THRA) resistance, disclosed a polymorphism (rs12939700) in a critical region involved in TRα alternative processing. DESIGN AND SUBJECTS: THRA gene variants were evaluated in three independent europid populations (i) in two population cohorts at baseline (n=3417 and n=2265), 6 years later (n=2139) and (ii) in 4734 high cardiovascular risk subjects (HCVR, PREDIMED trial). RESULTS: The minor allele of the index case polymorphism (rs12939700), despite having a very low frequency (4%), was significantly associated with higher body mass index (BMI) (P=0.042) in HCVR subjects. A more frequent THRA polymorphism (rs1568400) was associated with higher BMI in subjects from the population (P=0.00008 and P=0.05) after adjusting for several confounders. Rs1568400 was also strongly associated with fasting triglycerides (P dominant=3.99 × 10(-5)). In the same sample, 6 years later, age and sex-adjusted risk of developing obesity was significantly increased in GG homozygotes (odds ratio 2.93 (95% confidence interval, 1.05-6.95)). In contrast, no association between rs1568400 and BMI was observed in HCVR subjects, in whom obesity was highly prevalent. This might be explained by the presence of an interaction (P <0.001) among the rs1568400 variant, BMI and saturated fat intake. Only when saturated fat intake was high (>24.5 g d(-1)), GG carriers showed a significantly higher BMI than A carriers after controlling for energy intake and physical activity. CONCLUSIONS: THRA gene polymorphisms are associated with obesity development. This is a novel observation linking the THRA locus to metabolic phenotypes.