To evaluate the effect of short-term (12-h) high-volume hemofiltration (HVHF) in reversing progressive refractory hypotension and hypoperfusion in patients with severe hyperdynamic septic shock. To evaluate feasibility and tolerance and to compare observed vs. expected hospital mortality. Prospective, interventional, nonrandomized study in the surgical-medical intensive care unit of an academic tertiary center. Twenty patients with severe septic shock, previously unresponsive to a multi-intervention approach within a goal-directed, norepinephrine-based algorithm, with increasing norepinephrine (NE) requirements (>0.3 microg kg(-1) min(-1)) and lactic acidosis. Single session of 12-h HVHF. We measured changes in NE requirements and perfusion parameters every 4h during HVHF and 6h thereafter. Eleven patients showed decreased NE requirements and lactate levels (responders). Nine patients did not fulfill these criteria (nonresponders). The NE dose, lactate levels, and heart rates decreased and arterial pH increased significantly in responders. Hospital mortality (40%) was significantly lower than predicted (60%): 67% (6/9) in nonresponders vs. 18% (2/11) in responders. Of 12 survivors 7 required only a single 12-h HVHF session. On logistic regression analysis the only statistically significant predictor of survival was theresponse to HVHF (odds ratio 9). A single session of HVHF as salvage therapy in the setting of a goal-directed hemodynamic management algorithm may be beneficial in severe refractory hyperdynamic septic-shock patients. This approach may improve hemodynamics and perfusion parameters, acid-base status, and ultimately hospital survival. Moreover, it is feasible, and safe.