The effects and the mechanism of single and long-term administration of theophylline on ventilatory regulation were investigated in patients with chronic obstructive pulmonary disease (COPD). The ventilatory and mouth occlusion pressure (P0.1) responses during CO2 rebreathing were measured before and 4 hours after oral, single administration of theophylline in 15 patients with pulmonary emphysema, 15 patients with asthma and 10 healthy subjects. Ventilatory response to CO2 (VE/PCO2) was increased in patients with asthma and P0.1 response to CO2 (P0.1/PaCO2) was increased in patients with pulmonary emphysema after single theophylline administration. In patients with pulmonary emphysema, the increase in P0.1 was more marked than that in maximum inspiratory pressure static (MIPS). The effect of long-term administration of theophylline was studied in 8 patients with COPD and 8 patients with restrictive lung disease. In patients with COPD, P0.1/PaCO2 was significantly increased and the increase was maintained until three months later. These findings suggest that theophylline is effective in improving ventilatory and occlusion pressure responses to CO2 in patients with asthma probably by its bronchodilating effect, and in patients with pulmonary emphysema by its direct effect on the ventilatory control system.