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Observational studies link statin therapy with improved outcomes in patients with severe sepsis.To test whether atorvastatin therapy affects biologic and clinical outcomes in critically ill patients with severe sepsis.Phase II, multicenter, prospective, randomized, double-blind, placebo-controlled trial stratified by site and prior statin use. A cohort of 250 critically ill patients (123 statins, 127 placebo) with severe sepsis were administrated either atorvastatin (20 mg daily) or matched placebo.There was no difference in IL-6 concentrations (primary end point) between the atorvastatin and placebo groups (P= 0.76) and no interaction between treatment group and time to suggest that the groups behaved differently over time (P= 0.26). Baseline plasma IL-6 was lower among previous statin users (129 [87-191] vs. 244 [187-317] pg/ml;P= 0.01). There was no difference in length of stay, change in Sequential Organ Failure Assessment scores or mortality at intensive care unit discharge, hospital discharge, 28- or 90-day (15% vs. 19%), or adverse effects between the two groups. Cholesterol was lower in patients treated with atorvastatin (2.4 [0.07] vs. 2.6 [0.06] mmol/L;P= 0.006). In the predefined group of 77 prior statin users, those randomized to placebo had a greater 28-day mortality (28% vs. 5%;P= 0.01) compared with those who received atorvastatin. The difference was not statistically significant at 90 days (28% vs. 11%;P= 0.06).Atorvastatin therapy in severe sepsis did not affect IL-6 levels. Prior statin use was associated with a lower baseline IL-6 concentration and continuation of atorvastatin in this cohort was associated with improved survival.Clinical trial registered with the Australian New Zealand Clinical Trials Registry (ACTRN 12607000028404).