Adiponectin (adipoQ) gene variants have been associated with type 2 diabetes mellitus and insulin resistance. Our aim was to examine whether the presence of several polymorphisms at the adipoQ gene locus (-11391 G > A, -11377 C > G, 45 T > G, and 276 G > T) influences the insulin sensitivity to dietary fat. Healthy volunteers (30 men and 29 women) consumed 3 diets for 4 wk each: an initial period during which all subjects consumed a SFA-rich diet (38% total fat, 20% SFA), followed by a carbohydrate-rich diet (CHO) (30% total fat, 55% carbohydrate) or a monounsaturated fatty acid (MUFA)-rich diet (38% total fat, 22% MUFA) following a randomized, crossover design. After participants consumed each diet, we tested peripheral insulin sensitivity with the insulin suppression test and measured plasma adiponectin concentrations. C/C homozygous men for the -11377 C > G single nucleotide polymorphism (SNP) had a significantly greater decrease in the steady-state plasma glucose concentrations when changing from the SFA-rich (8.95 +/- 0.6 mmol/L) to the MUFA-rich (6.04 +/- 0.31 mmol/L) and CHO-rich (6.35 +/- 0.38 mmol/L) diets than did those carrying the minor G allele (SFA, 6.65 +/- 0.4 mmol/L; MUFA, 6.45 +/- 0.4 mmol/L; CHO, 5.83 +/- 0.3 mmol/L) (P sex x gene x diet interaction = 0.016). These differences did not occur in female participants. Furthermore, C/C men had lower plasma adiponectin concentrations than did C/C women (P sex x gene interaction = 0.015), independently of the dietary fat consumed. None of the variables examined were significantly associated with -11426 A > G, 45T > G, or 276 G > T SNP. In conclusion, C/C homozygous men for the -11377 C > G SNP at adipoQ gene were significantly less insulin resistant after consumption of the MUFA- and CHO-rich diets compared with the SFA-rich diet. This information should help in the identification of vulnerable populations or persons who will benefit from more personalized and mechanism-based dietary recommendations.