Aims/hypothesis. The UCP2-UCP3 gene region has been previously associated with obesity and diabetes. In a large representative cohort of Northern France (MONICA project), we studied the effect of a recently reported C/T polymorphism located in the 5' sequences of the UCP3 gene on anthropometric measurements and lipid profile. We also examined the association of this polymorphism with obesity and Type II (non-insulin-dependent) diabetes mellitus.¶Methods. The –55 C/T polymorphism of the UCP3 gene has been genotyped in 1155 subjects from the MONICA project. Association studies were done with diabetes, obesity and related phenotypes. Results were ascertained in a second cohort of well-characterized Type II diabetic and control subjects.¶Results. The variant T allele was associated with a decreased risk of developing Type II diabetes. Frequencies of the T allele were 13.3 % compared with 22 %, p = 0.04, in the diabetic and control groups, respectively. This observation was confirmed in the second cohort of French Type II diabetic (n = 171) and control (n = 124) subjects: 17.8 % compared with 25 %, p = 0.03. Moreover, subjects bearing the TT genotype had higher plasma total cholesterol and LDL-cholesterol concentrations (p = 0.0006 and p = 0.001, respectively) than subjects bearing wild or heterozygous genotypes.¶Conclusion/interpretation. The UCP3–55 C/T polymorphism was associated with a higher atherogenic profile and modified the risk for the development of Type II diabetes. [Diabetologia (2000) 43: 1424–1428]