Objective:To assess whether insulin sensitivity can explain the associations of leg-fat mass (LFM) and trunk-fat mass (TFM) with the cardiovascular disease (CVD) risk profile in healthy European men and women.Methods and Procedures:We studied 142 healthy men and women of a multicenter European study on insulin sensitivity, aged 30-60 years, from the centres in Hoorn, the Netherlands and Rome, Italy. Whole-body dual-energy X-ray absorptiometry (DXA) was used to determine fat and lean soft tissue mass in the trunk and legs. Fasting glucose, insulin, and lipid levels were measured. Insulin sensitivity (M/I-ratio) was measured during a euglycemic- hyperinsulinemic clamp. Associations between fat distribution and CVD risk factors were studied with linear regression analyses with adjustment for other body compartments, and subsequent adjustment for insulin sensitivity.Results:In men, larger LFM was significantly and independently associated with lower triglyceride levels (TGs) and higher high-density lipoprotein (HDL) cholesterol (P < 0.10) and tended to be associated also with lower low-density lipoprotein (LDL) cholesterol, and lower fasting insulin levels. In women, larger LFM was associated with favorable values of all CVD risk factors, although the associations were not statistically significant. In both sexes, larger TFM was independently and significantly associated with unfavorable values of most CVD risk factors, and most associations did not markedly change after adjustment for insulin sensitivity.Discussion:In a relatively young and healthy European population, larger LFM is associated with a lower and TFM with a higher cardiovascular and metabolic risk, which can not be explained by insulin sensitivity.