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To review the anti-inflammatory and anti-apoptotic properties of drotrecogin alfa (activated) (recombinant human activated protein C), emphasizing its modulatory effects on endothelial nuclear factor-κB. We propose a broad anti-inflammatory effect of drotrecogin alfa (activated), acting on both endothelium and monocytes.A selected review of the published literature on nuclear factor-κB, severe sepsis, and the use of drotrecogin alfa (activated) in clinical and preclinical models, together with data derived from preclinical gene profiling of model systems.Data from the PROWESS trial support the preclinical evidence of an antithrombotic effect of drotrecogin alfa (activated). Anti-inflammatory effects through reduction of thrombin generation and through thrombin-independent mechanisms in mononuclear and endothelial cells are reviewed. Inhibition of apoptosis is used as an example of the protective effect of drotrecogin alfa (activated) on endothelial and mononuclear cell dysfunction.Drotrecogin alfa (activated) acts as a modulator of nuclear factor-κB to aid in the host immune response in endothelium and monocytes. Extrapolation of gene array findings to explain apoptosis in endothelium and monocytes, coupled with emerging preclinical reports, provides evidence to support the role of drotrecogin alfa (activated) in modulating nuclear factor-κB.