Effects of theophylline administration on the respiratory drive were studied in seven patients with chronic obstructive pulmonary disease (COPD). End tidal CO2 (PetCO2), minute ventilation (Ve), forced expiratory volume in one second (FEV1), forced vital capacity (FVC), oxygen consumption (VO2), carbon dioxide output (VCO2), serum theophylline level (STL), ventilatory response (VeR), and mouth occlusion pressure response (OPR) to rise in PetCO2 on rebreathing were measured before and at 2-hour intervals after oral administration of 5 mg/kg anydrous theophylline or placebo. Mouth occlusion pressure response and VeR showed c significant increase after theophylline but not after placebo. Significant positive correlation between changes (delta) in STL and OPR (delta OPR = 0.025 + 0.8 delta STL; SEE = 1; r = 0.4; P < 0.005) and between STL and VeR (VeR = 0.82 + 0.055 STL +/- SEE = 0.7; r = 0.46; P < 0.01) and an inverse correlation between delta STL and delta PetCO2 (delta PetCO2 = 13.8 - 0.59 delta STL; SEE = 9.1; r = 0.61; P < 0.001) were noted. There was no correlation between the indices of respiratory drive and FEV1, Ve, VO2, or VCO2. It is concluded that theophylline increases respiratory drive in clinically employed doses independently of its bronchodilator or metabolic effects.