Experimental endotoxemia as a model of the initial septic response affects the autonomic nervous system with profound cardiovascular sequelae. Whether the postsynaptic sympathoneural activity to the muscle vascular bed is altered in the early septic phase remains to be determined. The present study aimed to elucidate the early effects of lipopolysaccharide (LPS) on muscle sympathetic nerve activity (MSNA) and cardiovascular regulation in healthy humans. Young healthy volunteers randomly received either an LPS-bolus (4ng/kg body weight, n=11) or placebo (saline; n=7). Experimental baroreflex assessment (baseline measurements followed by infusion of vasoactive drugs (nitroprusside / phenyl-ephrine) was done prior to and 90 min following LPS or placebo challenge. MSNA, heart rate, blood pressure and blood levels of catecholamines, TNF- and IL-6 were measured sequentially. Endotoxin but not placebo induced flu-like symptoms and elevated cytokine levels. In contrast to placebo, LPS significantly suppressed MSNA burst frequency 90 min after injection (mean±SEM: 12.1±2.9 vs. 27.5±3.3 burst/min (post vs. prior to LPS); p<0.005), but increased heart rate (78.4±3.1 vs. 60.6±2.0 beats/min (post vs. prior to LPS; p<0.001) . Baseline blood pressure was not altered, but baroreflex-testing demonstrated a blunted MSNA-response and uncoupling of heart rate modulation to blood pressure changes in the endotoxin-group. We conclude that endotoxin challenge in healthy humans has rapid suppressive effects on postsynaptic sympathetic nerve activity to the muscle vascular bed and alters baroreflex-function which may contribute to the untoward cardiovascular effects of sepsis.