To monitor the use of drotrecogin alfa activated (DrotAA) in Italy and its effects on patients' health. Prospective pharmaco-surveillance program with a parallel non-randomized control group. The Ministry of Health required all intensive care units (ICUs) using DrotAA to participate in the pharmaco-surveillance program. Our control group was formed of patients eligible for treatment with DrotAA but who had not received it. The data we collected included basic demographic characteristics, indications, modalities of use, adverse events, and ICU mortality. We identified potentially non-collaborating centres on the basis of data on DrotAA purchasing by hospitals. From 2003 to 2006, 668 cases of treatment with DrotAA were reported. We estimate that 79.3% of all patients treated in Italy in this period were recruited. Off-label use was common. Delayed start was the main reason for off-label prescription. Bleeding during infusion occurred in 73 patients (10.9%). The ICU mortality was higher in patients with bleeding (57.5 vs. 44.9%; p=0.041). Crude ICU mortality was lower in patients receiving DrotAA than in controls (46.4 vs. 54.9%; p=0.0004); however, multivariate analysis, which adjusted for certain relevant differences, showed that DrotAA treatment was associated with higher mortality after scheduled surgery. These results question the way in which the drug is used in everyday clinical practice and its efficacy in a selected subgroup, and reinforce the need for a new, independent, confirmatory trial to reassess the risk-to-benefit ratio of DrotAA.