OBJECTIVE: To evaluate whether a 5-week low-glycemic index (LGI) diet versus a high-glycemic index (HGI) diet can modify glucose and lipid metabolism as well as total fat mass in nondiabetic men. RESEARCH DESIGN AND METHODS: In this study, 11 healthy men were randomly allocated to 5 weeks of an LGI or HGI diet separated by a 5-week washout interval in a crossover design. RESULTS: The LGI diet resulted in lower postprandial plasma glucose and insulin profiles and areas under the curve (AUCs) than the HGI diet. A 5-week period of the LGI diet lowered plasma triacylglycerol excursion after lunch (AUC, P < 0.05 LGI vs. HGI). These modifications were associated with a decrease in the total fat mass by approximately 700 g (P < 0.05) and a tendency to increase lean body mass (P < 0.07) without any change in body weight. This decrease in fat mass was accompanied by a decrease in leptin, lipoprotein lipase, and hormone-sensitive lipase RNAm quantities in the subcutaneous abdominal adipose tissue (P < 0.05). CONCLUSIONS: We concluded that 5 weeks of an LGI diet ameliorates some plasma lipid parameters, decreases total fat mass, and tends to increase lean body mass without changing body weight. These changes were accompanied by a decrease in the expression of some genes implicated in lipid metabolism. Such a diet could be of benefit to healthy, slightly overweight subjects and might play a role in the prevention of metabolic diseases and their cardiovascular complications.