BACKGROUND: Drotrecogin alfa (activated) DrotAA is approved for the reduction of mortality in adults with severe sepsis (sepsis with acute organ dysfunction) and high risk of death. Patients whose actual body weight was >135 kg were excluded from the Phase III PROWESS trial. OBJECTIVE: To compare exposure to DrotAA in patients with severe sepsis weighing >135 kg with those weighing ⩽135 kg in an open-label, Phase IV trial, and quantify the elimination half-life (t1/2) of DrotAA in these patients. METHODS: PROWESS inclusion/exclusion criteria were used, except that patients >135 kg were enrolled. Blood samples were collected for steady-state plasma concentration (Css) analysis of activated protein C once each day and for t1/2 analysis after infusion. Weight-normalized clearance (Clp) and t1/2 estimates for DrotAA were calculated and compared between weight groups. RESULTS: Patient weight range was 59–227 kg. There were 32 patients ⩽135 kg and 20 patients >135 kg enrolled. Median Clp was 0.45 L/h/kg (interquartile range IQR 0.37–0.54) for patients ⩽135 kg and 0.42 L/h/kg (IQR 0.33–0.54) for patients >135 kg (p = 0.692). Median estimates of Css were 51.9 ng/mL (IQR 43.4–62.0) and 56.5 ng/mL (IQR 44.9–71.1; p = 0.570). In patients ⩽135 kg, DrotAA had a median t1/2 of 16.7 minutes (IQR 13.9–20.0) compared with 16.0 minutes (IQR 12.9–19.8) in patients >135 kg (p = 0.767), for a composite median t1/2 of 16.3 minutes (IQR 14.2–18.8). CONCLUSIONS: There is no statistically significant difference in Css concentrations or t1/2 of DrotAA between patients weighing ⩽135 kg and >135 kg. DrotAA should be dosed by actual body weight.