The association between the genotypes and the alleles at the A, B or C locus of the HLA system and body fat was studied in a total of 1578 individuals subdivided in four cohorts: adult males (n greater than or equal to 204), adult females (n greater than or equal to 184), boys and male adolescents (n greater than or equal to 282), and girls and female adolescents (n greater than or equal to 257). None of these subjects were grossly obese or had known metabolic disorders. Percent body fat from underwater weighing, subcutaneous fat from 6 skinfold measurements, trunk fat (3 skinfolds) and extremity fat (3 skinfolds) were considered in the analysis. Although a few significant associations were encountered, the lack of consistency across samples suggested that they were probably random and biologically not meaningful. The same negative findings were found for the ratio of trunk subcutaneous fat to extremity subcutaneous fat and the ratio of subcutaneous fat (6 skinfolds) to total fat mass. Earlier reports indicating a significant association between high body fat content and antigens B18, Bw35 or Cw4 were not supported by the results of this study. It was concluded that no consistent pattern of association emerged between genotypes or alleles of the HLA system and percent body fat, subcutaneous fat or fat distribution in children and adults of both sexes.