Aims/hypothesis. The region 2p21–23, containing the proopiomelanocortin gene (POMC), was reported to be linked to leptin concentrations in Mexican-American, French and African-American cohorts. A polyhormone peptide, POMC is expressed in brain, gut, placenta and pancreas. The POMC mutations are responsible for rare cases of early-onset obesity. Thus we examined the contribution of the POMC locus to obesity in French families. Methods. Single and multipoint linkage studies were done between obesity, obesity associated-phenotypes (leptin values and z-score of the body mass index) and three newly mapped markers surrounding POMC in 264 affected sib-pairs from French obese families. Mutation screening of the exons and intron/exon junctions of the POMC gene was realised by direct sequencing. Association studies were done in 379 unrelated obese patients and 370 non-obese non-diabetic subjects. Results. Linkage analysis confirmed the trend towards linkage between polymorphic markers around POMC and variations of leptin concentrations and z-score (maximum lod score at D2S2337 = 2.03). Mutation screening of the POMC gene in the French Caucasian cohort identified two previously reported polymorphisms. None of these variants was associated with obesity, diabetes or serum leptin and lipid concentrations. Conclusion/interpretation. Our results indicate that mutations in the POMC gene do not contribute to the variance of obesity associated phenotypes, at least in French Caucasians. Given the replicated evidence of linkage between leptin values and the chromosome 2p21–23 region in different populations, it is likely that functional variant(s) in the POMC regulating sequences or in an unknown gene in this region explains this linkage. [Diabetologia (2000) 43: 1554–1557]