Childhood and adult obesity have been widely associated with FTO genetic variability in different populations. This study aimed to investigate the linkage disequilibrium (LD) block structure of a region surrounding the candidate rs9939609 SNP and determine the best single nucleotide polymorphism (SNP) combination that explains the higher proportion of variability observed in children with severe obesity, including obese subjects from families with a very high occurrence of obesity. A sliding window approach pointed to a block containing the rs1477196/rs17817449/rs9939609 haplotype (P value 3.1 × 10(-8)). Carriers of the GGA combination had an increased risk of obesity (odds ratio (OR) 2.07, 95% confidence interval (CI) 1.41-3.04, P = 2.0 × 10(-4)) with respect to those individuals with the reference ATT haplotype. A further SNP, rs9921255, also showed association with obesity (P = 8.3 × 10(-4), OR 1.77; 95% CI 1.15-2.74 and OR 5.78; 95% CI 1.22-27.49 for heterozygotes and homozygotes, respectively) and did not segregate with the previously described risk haplotype. The calculation of risk score based on the GGA haplotype combined with the rs9921255 variant showed a much greater effect of the FTO gene on high BMI. This score yields an attributable risk of 34% for severe obesity, and the increased risk per risk allele was 1.71 (P = 1.0 × 10(-6)). We conclude that the description of this polymorphic combination in the FTO gene could be useful for the early identification of inherited susceptibility to weight-gain since childhood, with a higher sensitivity than considering the effect of a single marker.