The use of Drotrecogin alfa (DAA) (Xigris) in select patients with sepsis has had demonstrable improvement in survival, though its benefit in necrotizing soft tissue infections (NSTI) is unclear. A retrospective review of NSTI patients receiving DAA at our institution from 2006 to 2009 was performed. Our previously derived mortality prediction model, based on classification and regression tree analysis, was applied to patients and the predicted mortality was compared with the actual mortality rate. Ten patients with severe NSTI received DAA. The median admission values were: white blood cell count of 27,000/mm3, serum lactate of 4.0 mmol/L, and serum sodium of 128 mEq/L. Four (40%) patients had systemic complications, five (50%) patients required amputation, and one died (10%). Median time to DAA administration was 12 hours after debridement. There were no bleeding complications attributed to DAA use. Mortality in this series of severe NSTI was only 10 per cent, which compares favorably with the predicted mortality of 18 per cent based on classification and regression tree analysis (P = 0.2). A prospective, randomized study is warranted to determine if the use of DAA should be part of the standard therapy for NSTI patients with a predicted high mortality.