Study objectives: To investigate the nature and extent of the alteration in autonomic function following heterotopic lung transplantation. Design: Measures of cardiac parasympathetic nervous system activity (PNSA) and systemic sympathetic nervous system activity (SNSA) were compared in lung transplant patients and age-matched healthy subjects, both at rest and following autonomic perturbation. Setting: Lung transplantation service of a university teaching hospital. Patients and participants: Twenty-two lung transplant patients (mean [+/- SEM] age, 50.5 +/- 2.4 years) and 13 healthy subjects (mean age, 48.2 +/- 3.7 years). Measurements and results: Lung transplant patients had decreased baseline time and frequency domain measures of heart rate variability compared to healthy subjects (root mean square of successive differences in R-R intervals, 11.2 +/- 1.1 vs 30.3 +/- 4.5 ms, respectively [p < 0.0051; LnHP, 2.4 +/- 0.2 vs 4.8 +/- 0.4 ms, respectively [p < 0.0051). In addition, lung transplant patients demonstrated an attenuated reduction in LnHP/LnTP following head-up tilt in comparison to healthy subjects (p < 0.05). The baseline recumbent plasma norepinephrine level was increased in lung transplant patients compared to healthy subjects (3.25 +/- 0.43 vs 2.00 +/- 0.27 nmol/L, respectively; p < 0.05), and levels increased in both groups with upright head-up tilt. There were no differences between the two groups in heart rate or mean systolic BP responses to both the Valsalva maneuver and cold pressor testing. Conclusions: Lung transplant patients have both reduced PNSA and increased SNSA at rest. Furthermore, these patients appear to have a preserved capacity to respond to autonomic perturbation by increasing SNSA. The mechanisms underlying these observations and their prognostic implications remain to be determined.