BACKGROUND: Moxonidine, an imidazoline I1 receptor agonist, is a centrally acting antihypertensive agent having sympatholytic effect. However, there are only limited data regarding the effects of this drug on autonomic cardiac functions. METHODS AND RESULTS: In this study we investigated the acute effects of moxonidine on cardiac autonomic modulation by heart rate variability (HRV) analysis. The effects of oral 0.4-mg moxonidine were studied on 11 healthy male volunteers in a randomized, double-blind, placebo controlled, and crossover study. After 15 minutes rest, time and frequency domain parameters of HRV were calculated from 5-minute continue electrocardiography recordings in supine position, during controlled respiration (15 breath/min) and during handgrip exercise before and 1 hour after taking placebo or moxonidine. Baseline parameters before taking placebo and moxonidine were similar (P > 0.05). Moxonidine, but not placebo, caused an increase in heart failure (HF) (119 +/- 21 vs 156 +/- 23, P = 0.029) and HFnu (39 +/- 4 vs 47 +/- 4, P = 0.033) and decrease in LFnu (61 +/- 4 vs 53 +/- 4, P = 0.033) and LF/HF ratio (1.96 +/- 0.36 vs 1.12 +/- 0.35, P = 0.010) in supine position compared with baseline parameters. However, there was no difference in other time or frequency domain parameters during controlled breathing and handgrip exercise either with moxonidine or placebo administration (P > 0.05). Single dose of moxonidine administration increases cardiovagal tone but parasympathetic and sympathetic autonomic maneuvers attenuated its short term effects on HRV in healthy male subjects.