Almitrine bismesylate improves arterial blood gases in patients with chronic obstructive pulmonary disease (COPD), but side effects such as increase of ventilatory drive and dyspnea have been reported in some studies. We studied 18 COPD patients (mean age = 59.1 years; mean FEV1 = 0.92 1; mean PaO2 = 58.6 mmHg) in a double-blind randomized study using placebo or almitrine 50 mg twice a day by mouth, for 60 days. In contrast to the placebo group, 40% of the patients in the almitrine group presented a significant increase in PaO2 and a decrease in P(A-a)O2 > or = 5 mmHg during submaximal exercise after 60 days of treatment. Ventilatory drive and the breathing pattern were measured at rest and during submaximal exercise. Both groups showed high levels of ventilatory drive and a tachypneic breathing pattern before drug treatment and no modification was found 30 and 60 days after treatment. Metabolic, cardiovascular and ventilatory variables were studied during an incremental to maximum exercise symptom-limited test (cycloergometry). Maximal VO2 ranged from 46 to 52% and heart rate from 76 to 78% in relation to the predicted values. The percent ratio of ventilation at maximal exercise to maximal voluntary ventilation at rest ranged from 86 to 94%. These results show that the reduction of ventilatory capacity was the main factor decreasing the aerobic performance of our COPD patients. Maximal exercise tolerance (VO2 max) did not change after almitrine treatment. Negative factors like an increase in neuromuscular drive did not occur, and positive factors like an increase in PaO2 and oxygen transport had no critical influence on exercise performance in our ventilatory-limited COPD patients.