To evaluate possible autonomic nervous system (ANS) dysfunction in patients with chronic obstructive pulmonary disease (COPD) in the absence of any hypoxic neuronal damage, we studied 31 patients with COPD patients aged 31 to 68 years (55 +/- 10) and 32 age-matched healthy subjects (control). Respiratory function in the patients was as follows: FEV1 = 52 +/- 8 percent; PaO2 = 71 +/- 14 mm Hg; and PaCO2 = 40 +/- 10 mm Hg. The ANS was assessed by heart rate variability (HRV) in the time domain (SD of mean RR interval) and frequency domain (autoregressive spectral analysis recognizing low [LF] and high [HF] frequency components, vagal and sympathetic related, respectively). Patients and controls were evaluated at rest and during vagal (controlled breathing [CB]) and sympathetic (passive head-up tilt) maneuvers. Patients with COPD showed a depressed global HRV (rest SD = 34 +/- 20 ms vs 45 +/- 15 ms, p < 0.05; tilt SD = 28 +/- 14 ms vs 38 +/- 13, p < 0.01) with a predominant respiratory drive (rest HF = 44 +/- 28 vs 28 +/- 18, p < 0.05; tilt HF 42 +/- 28 vs 16 +/- 12, p < 0.01) as compared with normal subjects. In the control group, vagal and sympathetic responses were in opposite directions following a stimulus, whereas there was no significant HRV response in the COPD group. We conclude that patients with COPD have abnormalities of ANS function, with in particular a depressed HRV response to sympathetic and vagal stimuli.