Activation of the vestibular otolith organs with head-down rotation increases muscle sympathetic nerve activity (MSNA) in humans. Previously, we demonstrated this vestibulosympathetic reflex (VSR) elicits increases in MSNA during baroreflex unloading (i.e., lower-body negative pressure) in humans. Whether such an effect persists during baroreflex loading is unknown. We tested the hypothesis that the ability of the VSR to increase MSNA is preserved during baroreflex unloading and inhibited during baroreflex loading. Ten subjects (26±1 yr) performed 3 trials of head-down rotation (HDR) to activate the VSR. These trials were performed after a period of sustained saline (control), nitroprusside (baroreflex unloading: 0.8-1.0 µg/kg/min), and phenylephrine (baroreflex loading: 0.6-0.8 µg/kg/min) infusion. Nitroprusside infusion decreased (7±1 mmHg; p<0.001) and phenylephrine infusion increased mean arterial pressure (8±1 mmHg; p<0.001) at rest. HDR performed during the control (3±2 bursts/min, 314±154 arbitrary units (au) total activity, 41±18% total activity; p<0.05) and nitroprusside trials (5±2 bursts/min, 713±241 au total activity, 49±20% total activity; p<0.05) increased MSNA similarly despite significantly elevated levels at rest (13±2 to 26±3 bursts/min) in the latter. In contrast, HDR performed during the phenylephrine trial failed to increase MSNA (0±1 bursts/min, -15±33 au total activity, -8±21% total activity). These results confirm previous findings that the ability of the VSR to increase MSNA is preserved during baroreflex unloading. In contrast, the ability of the VSR to increase MSNA is abolished during baroreflex loading. These results provide further support for the concept that the VSR may act primarily to defend against hypotension in humans.