OBJECTIVE: To determine the effect of a high-protein (HP) diet compared with a low-protein (LP) diet on weight loss, resting energy expenditure (REE), and the thermic effect of food (TEF) in subjects with type 2 diabetes during moderate energy restriction. RESEARCH DESIGN AND METHODS: In this study, 26 obese subjects with type 2 diabetes consumed a HP (28% protein, 42% carbohydrate) or LP diet (16% protein, 55% carbohydrate) during 8 weeks of energy restriction (1,600 kcal/day) and 4 weeks of energy balance. Body weight and composition and REE were measured, and the TEF in response to a HP or LP meal was determined for 2 h, at weeks 0 and 12. RESULTS: The mean weight loss was 4.6 +/- 0.4 kg (P < 0.001), of which 4.5 +/- 0.4 kg was fat (P < 0.001), with no effect of diet (P = 0.6). At both weeks 0 and 12, TEF was greater after the HP than after the LP meal (0.064 vs. 0.050 kcal x kcal(-1) energy consumed x 2 h(-1), respectively; overall diet effect, P = 0.003). REE and TEF were reduced similarly with each of the diets (time effects, P = 0.02 and P < 0.001, respectively). CONCLUSIONS: In patients with type 2 diabetes, a low-fat diet with an increased protein-to-carbohydrate ratio does not significantly increase weight loss or blunt the fall in REE.