Inadequate tissue oxygenation may occur in critically ill patients with sepsis despite an apparently adequate O2 transport (Q̇O2), and this may contribute to the development of an O2 debt and also to multiple organ failure. It has been shown that increasing Q̇O2 by infusing a vasodilator may reveal this O2 debt in septic patients. To investigate whether the site of action of vasodilators may be of importance in unmasking such an O2 debt, we administered prostacyclin, a prostaglandin with a preferential effect on the microcirculation, and phentolamine, an arteriolar vasodilator, in 11 patients studied during the first 48 hours after the onset of sepsis, and compared their effect on whole body oxygen consumption (V̇O2) and skin microvascular blood flow. The results demonstrated that increasing Q̇O2 by prostacyclin but not by phentolamine significantly increases V̇O2 in critically ill patients with sepsis. The site of action of vasodilators may therefore play an important role in their ability to unmask an O2 debt.