Combining metformin and exercise is recommended for the treatment of insulin resistance. However, it has been suggested that metformin blunts the insulin-sensitizing effects of exercise. We evaluated in a group of insulin-resistant patients the interactions between exercise and their daily dose of metformin. Ten insulin-resistant patients underwent insulin sensitivity assessment using intravenous glucose tolerance test after an overnight fast in the following conditions: (1) after taking their habitual morning dose of metformin (MET), (2) after 45 min of high intensity interval exercise having withheld metformin during 24 h (EX), and (3) after their habitual metformin dose plus an identical exercise bout (MET + EX). During the exercise trials (EX and MET + EX), energy expenditure and substrate oxidation were assessed by indirect calorimetry. In addition, 12-h postprandial blood glucose was measured in all three trials. Insulin sensitivity was similar between MET and EX [4.0 ± 0.8 and 4.1 ± 0.7 × 10(-4) min(-1) (μU mL)(-1); P = 0.953] but was 43 % higher than both MET and EX after MET + EX (NS; P = 0.081). Blood glucose disappearance rate was higher after MET + EX than after MET or EX trials (1.7 ± 0.2, 1.0 ± 0.1, and 1.2 ± 0.1 % min(-1), respectively; P = 0.020). There was no difference in postprandial blood glucose concentration after the three meals that followed the trials (P = 0.446). Exercise energy expenditure was 9 % higher during MET + EX than during EX (P = 0.015) partly due to increased carbohydrate oxidation. Our data suggest that habitual metformin treatment in insulin-resistant patients does not blunt the acute insulin-sensitizing effects of a single bout of exercise that on the contrary, tends to enhance it.