Obesity-related phenotypes have been linked to human chromosomes 1q21 and 20q13, regions where the lamin A/C gene (LMNA) and the melanocortin 3 receptor gene (MC3R) map, respectively. Recently, a common single nucleotide polymorphism (SNP) in LMNA (1908C/T) was associated with plasma leptin and obesity indices in aboriginal Canadians, but these associations have not yet been explored in other populations. In contrast, no significant associations of MC3R variants with obesity have been detected, although a significant association with hyperinsulinemia has been reported in Caucasian populations. We investigated the associations between the LMNA 1908C/T variant and the 241G/A variant of the MC3R gene (Val81Ile missense mutation) and body composition, as well as plasma leptin and insulin levels, in two samples of unrelated healthy Greek subjects. A group of 112 young nonobese subjects, and a group of 116 adult women with a body mass index (BMI) ranging from 23.2 to 47.7 kg/m2 were studied cross-sectionally. We found no significant association of the LMNA 1908C/T and a borderline significant association of MC3R 241G/A SNPs with body composition variables, in the entire study sample. However, unlike the LMNA 1908C/T genetic variation, the MC3R 241G/A genetic variation was significantly associated with hyperleptinemia and huperinsulinemia in obese subjects, and there was evidence of interaction between this polymorphism and fat mass or BMI in predicting hyperinsulinemia. Our results suggest that the LMNA 1908C-->T substitution and the Val81Ile mutation of the MC3R gene are unlikely to be major predictors of body composition in Greek Caucasians, but the latter genetic variation may predispose obese subjects to develop insulin and leptin resistance. Future studies are needed to confirm these data and assess whether individuals carrying this mutation are more resistant to weight-reducing and insulin-sensitizing treatments.