Obesity is a growing health problem in the U.S. As a complex trait, obesity involves multiple genes and gene-gene and gene-environment interactions that contribute to its pathogenesis. Here we report significant linkage from a scan of a large sample segregating extreme obesity and normal weight. We have used 382 microsatellite markers in 1,297 individuals from 260 European-American families. We conducted nonparametric linkage (NPL) analyses for dichotomous BMI (using BMI >/=27, >/=30, >/=35, and >/=40 kg/m(2)) using Genehunter. We also analyzed quantitative traits (BMI, percentage of fat, and waist circumference) by the family regression method using Merlin_regress. We found evidence for linkage on chromosome 12 (125 cM, D12S2070, logarithm of odds [LOD] 3.79, P = 0.00001 for percentage of fat; LOD 2.98, P = 0.0001 for BMI; and LOD 2.86, P = 0.00014 for waist circumference) by family regression analyses. Adding three additional markers to the intervals flanking the chromosome 12 peak yielded an LOD score of 4.08 (P = 0.00001) for percentage of fat at 116 cM and LOD scores of 3.57 (P = 0.00003) and 3.05 (P = 0.00009) for BMI and waist circumference, respectively, at 125 cM. We also obtained other suggestive linkages on chromosomes 2, 3, 7, 8, 9, 12, 13, and 21. Our results suggest multiple loci that could influence obesity, particularly a locus in chromosome region 12q23-24.