Selegiline (L-deprenyl), a selective inhibitor of monoamine oxidase type B, is an established adjuvant to levodopa therapy in Parkinson's disease (PD). To evaluate whether selegiline also effects the severity and progression of autonomic nervous system dysfunction in PD, we studied autonomic functions by measuring cardiovascular responses to normal breathing, deep breathing, the Valsalva maneuver, the tilting test, and the isometric contraction test prospectively in 52 PD patients receiving either selegiline (n = 27) or placebo (n = 25) in randomized order in a double-blind parallel trial. The study also continued double-blind after the introduction of levodopa. Recordings of cardiovascular responses were carried out annually, with the median follow-up period being 6 years. Cardiovascular autonomic reflexes were diminished in the patient groups compared with those of healthy control subjects (n = 45). There was no progression (except age-related) in dysautonomia in patients on placebo, but there was a decrease in cardiovascular responses in the selegiline group. The heart rate variability in normal breathing, in the Valsalva maneuver, and in the tilting test was clearly diminished during the selegiline treatment. In addition, in the tilting test, the fall in diastolic blood pressure immediately after tilting and in systolic blood pressure 2 minutes after standing up was more pronounced in the selegiline group than in the placebo group. Levodopa treatment had no effect on the measured autonomic responses. In the isometric contraction test, the two treatment groups showed no difference. We conclude that selegiline treatment diminishes autonomic responses, especially those of the sympathetic division. This sympatholytic effect may signal an increased risk of orthostatic hypotension.