In patients with sepsis and systemic inflammatory response syndrome, hemodynamic support is often complicated by a vascular hyporesponsiveness to exogenously administered norepinephrine. Although norepinephrine tachyphylaxis represents a significant clinical problem, the relationship between norepinephrine dosages and mean arterial pressure (MAP) in the presence of systemic inflammation is still not fully understood. This study was, therefore, designed as a prospective, controlled laboratory trial to elucidate the hemodynamic response to incremental norepinephrine doses in healthy and endotoxemic sheep. ANOVA demonstrated that a significantly higher mean infusion rate of norepinephrine was needed to increase MAP by 20 mmHg in endotoxemic versus healthy control sheep (P = 0.007). Whereas the goal-MAP was reached in 100% of healthy controls, it was achieved in only 80% during endotoxemia. Cardiac index increased significantly in healthy, but not in endotoxemic, sheep. Our findings confirm the presence of vascular hyporesponsiveness to norepinephrine in endotoxemia. In addition, this study demonstrates that the presence of systemic inflammation leads to an early hyporesponsiveness against norepinephrine which was caused by a drug-independent mechanism rather than a tachyphylaxis due to long-term administration of norepinephrine.