OBJECTIVE: Free fatty acid (FFA) oxidation is reduced in subjects with type 2 diabetes mellitus and impaired glucose tolerance (IGT). Weight reduction does not improve these impairments. Because exercise training is known to increase fatty acid (FA) oxidation, we investigated whether a combined diet and physical activity intervention program can improve FA oxidation in subjects with IGT. RESEARCH METHODS AND PROCEDURES: Sixteen subjects with IGT were studied before and after 1 year of a lifestyle intervention program [nine intervention (INT) subjects, seven controls (CON)]. INT subjects received regular (i.e., every 3 months) dietary advice and were stimulated to increase their level of physical activity. Glucose tolerance, anthropometric characteristics, and substrate use at rest and during exercise were evaluated before and after 1 year. Substrate oxidation was measured at rest and during moderate intensity exercise using indirect calorimetry in combination with stable isotope infusion ([U-(13)C]palmitate and [6,6-(2)H(2)-]glucose). RESULTS: After 1 year, no differences were seen in substrate use at rest. During exercise, total fat and plasma FFA oxidation were slightly increased in the INT group and decreased in the CON group, with the change being significantly different (change after 1 year: INT, +2.0 +/- 1.4 and +1.9 +/- 0.9 micromol/kg per minute; CON, -3.5 +/- 1.6 and -1.8 +/- 0.5 micromol/kg per minute for total and plasma FFA, respectively; p < 0.05). DISCUSSION: A combined diet and physical activity intervention program can prevent further deterioration of impaired FA oxidation during exercise in subjects with IGT.