The A-allele of the single nucleotide polymorphism (SNP), rs9939609, in the FTO gene is associated with increased fatness. We hypothesized that the SNP is associated with morbidity and mortality through the effect on fatness. METHODOLOGY/PRINCIPAL FINDINGS: In a population of 362,200 Danish young men, examined for military service between 1943 and 1977, all obese (BMI>or=31.0 kg/m(2)) and a random 1% sample of the others were identified. In 1992-94, at an average age of 46 years, 752 of the obese and 876 of the others were re-examined, including measurements of weight, fat mass, height, and waist circumference, and DNA sampling. Hospitalization and death occurring during the following median 13.5 years were ascertained by linkage to national registers. Cox regression analyses were performed using a dominant effect model (TT vs. TA or AA). In total 205 men died. Mortality was 42% lower (p = 0.001) with the TT genotype than in A-allele carriers. This phenomenon was observed in both the obese and the randomly sampled cohort when analysed separately. Adjustment for fatness covariates attenuated the association only slightly. Exploratory analyses of cause-specific mortality and morbidity prior to death suggested a general protective effect of the TT genotype, whereas there were only weak associations with disease incidence, except for diseases of the nervous system. CONCLUSION: Independent of fatness, the A-allele of the FTO SNP appears to increase mortality of a magnitude similar to smoking, but without a particular underlying disease pattern barring an increase in the risk of diseases of the nervous system.