OBJECTIVE: The link between the autonomic nervous system and restless legs syndrome (RLS) has been recently postulated. Since dopaminergic agents are used as first-line treatment for RLS, the purpose of our study is to verify whether chronic pramipexole treatment could influence the autonomic control of cardiovascular reflexes and heart rate variability (HRV) in RLS during wakefulness. METHODS: Consecutive drug naive RLS patients underwent polysomnography (PSG), subjective scales, and cardiovascular function tests including head-up tilt test (HUTT), Valsalva maneuver, deep breathing, handgrip and cold face before and after 3-month pramipexole therapy. HRV analysis was performed in the frequency domain using both autoregressive and fast Fourier transform algorithms in rest supine condition and during HUTT. RESULTS: Twenty RLS patients reported a significant reduction of RLS symptoms after pramipexole treatment, while PSG did not show significant improvements except for periodic limb movement index. Pramipexole induced a trend to a lower systolic blood pressure and a significant higher variation of systolic and diastolic blood pressure at HUTT. Cardiovascular responses to the other tests were unchanged. No significant differences in HRV spectral analysis between drug naive and treated patients were observed. Moreover, the within-group analysis of HRV between orthostatic and supine position did not show any significant change in sympathetic and parasympathetic components both in the drug naive and pramipexole groups. CONCLUSIONS: Chronic pramipexole treatment does not seem to affect autonomic balance during wakefulness. Considering that neither PSG data nor autonomic parameters are significantly modified by pramipexole, we hypothesize a non-dopaminergic autonomic dysfunction in RLS.