Non-insulin-dependent diabetes mellitus (NIDDM) is a complex metabolic disorder with a significant genetic component. Obesity is a frequent complicating factor for NIDDM. In the mouse, a number of single gene defects that result in obesity have been described. Mutations in one of these genes, the ob gene, results in both obesity and NIDDM. Recently, the cloning of the murine ob gene and its human homologue has been reported (Nature 372:425-432, 1994). In the present study, the contribution of genetic variation at the human ob locus to NIDDM susceptibility was assessed by analyzing allele sharing in NIDDM-affected sib pairs (ASPs) for markers located near the human ob gene. Four yeast artificial chromosome clones containing the human ob gene were isolated. These clones colocalized the ob gene and two microsatellite markers, D7S514 and D7S635, to a region of 280 kb on the long arm of human chromosome 7. The microsatellite markers were typed in 346 Mexican-American NIDDM-ASPs derived from 176 families and an additional 110 ethnically and geographically matched controls. No evidence of linkage or association between either microsatellite marker and NIDDM was observed in this population. These results suggest genetic variation in the human ob gene does not play a major role in susceptibility to NIDDM in Mexican-Americans.