The cloning of the murine obese (ob) gene and its human homologue has recently been reported. Mutations in the mouse ob gene result in hereditary obesity; however, the role of variations of OB in the regulation of bodyweight in humans has yet to be determined. The contribution of putative genetic variations in the human OB gene to total and regional fat mass in a normal twin population has been analyzed through linkage and association with a novel polymorphic marker, located in proximity to this gene. The polymorphic dinucleotide repeat, isolated from a P1 clone containing the human OB gene, was physically localized by long-range restriction mapping to within 30 kilobases of the OB locus. The marker was genotyped in a population of 47 healthy female/female dizygotic (DZ) twin pairs for which direct measures of central abdominal and whole body fat had been obtained by dual X-ray absorbtiometry. Possible linkage between the microsatellite marker and whole-body (p = 0.008), but not central abdominal (p = 0.09), fat deposits was indicated. No association between fat depot phenotype and marker genotype was detected. These results suggest that genetic variation in or close to the human OB gene may play a role in the size of body fat stores in healthy women.