Abstract: The present invention provides pharmaceutical compositions useful for the prevention and treatment of sepsis and other conditions such as stroke, reperfusion injury and heart attacks, containing 1) at least one macromolecular polysaccharide selected from the group consisting of hydroxyethyl starch, dextran, glycogen and mixtures thereof and 2) activated protein C. The compositions can further comprise at least one member selected from the group consisting of at least one antioxidant and/or at least one anti-infective. The present invention further provides methods of treating human subjects prior to or during sepsis and other conditions such as stroke, reperfusion injury and heart attacks to prevent leakage of macromolecules from capillary endothelial junctions and simultaneously prevent thrombosis and fibrin formation, reduce inflammation and improve microcirculation by intravenously administering to a subject in need of such treatment an effective amount of the said composition.