The purpose of this study was to examine the effect of dimenhydrinate on resting muscle sympathetic nerve activity (MSNA), the vestibulosympathetic reflex, and the baroreflexes. Sixteen subjects participated in two double-blinded studies that measured mean arterial pressure (MAP), heart rate (HR), and MSNA responses before and after oral administration of dimenhydrinate (100 mg) or a placebo. In study one, 3 min of head-down rotation (HDR) was performed to engage the otolith organs. Dimenhydrinate (n = 10) did not alter resting MSNA, MAP, or HR. HDR increased MSNA before (Delta5 +/- 1 bursts/min; P < 0.01) and after (Delta4 +/- 1 bursts/min; P < 0.01) drug administration, but these responses were not different from the placebo (n = 6). In study two, 4 min of lower body negative pressure (LBNP) at -30 mmHg was performed. During the third min of LBNP, HDR was performed. MSNA increased during the first 2 min of LBNP before (Delta13 +/- 2 bursts/min; P < 0.01) and after (Delta14 +/- 2 bursts/min; P < 0.01) dimenhydrinate. HDR combined with LBNP increased MSNA further during the third min of LBNP (Delta18 +/- 2 bursts/min before and Delta17 +/- 2 bursts/min after dimenhydrinate; P < 0.01). These responses were not significantly different from the placebo. In contrast, HR responses to LBNP during the dimenhydrinate trial were increased when compared to all other trials (Delta5 +/- 1 beats/min; P < 0.01). These results indicate that dimenhydrinate augments heart rate responses to baroreceptor unloading, but does not alter resting MSNA, the sympathetic baroreflexes, or the vestibulosympathetic reflex.