Disseminated intravascular coagulation (DIC) is a serious condition associated with sepsis. Clinical management of DIC is hampered by lack of clear diagnostic criteria. The International Society on Thrombosis and Haemostasis (ISTH) has proposed a diagnostic scoring algorithm for overt DIC based on routine laboratory tests. The objective was to assess a modified version of the ISTH scoring system and determine the effect of drotrecogin alfa (activated) (DrotAA, recombinant human activated protein C) on patients with DIC. The large database from the PROWESS clinical trial in severe sepsis was retrospectively used to assess a modified ISTH scoring system. Baseline characteristics and treatment effects of DrotAA were evaluated. At baseline, 29% (454/1568) of patients had overt DIC. Overt DIC was a strong predictor of mortality, independent of APACHE II score and age. Placebo-treated patients with overt DIC had higher mortality than patients without (43 vs. 27%). DrotAA-treated patients with overt DIC had a trend towards greater relative risk reduction in mortality than patients without (29 vs. 18%, P = 0.261) but both groups had greater relative risk reduction than placebo-treated patients. Serious bleeding rates during DrotAA infusion in patients with and without overt DIC were slightly increased (P = 0.498), compared with placebo, while clinically overt thrombotic events during the 28-day period were slightly reduced (P = 0.144). Modified ISTH overt DIC scoring may be useful as an independent assessment for identifying severe sepsis patients at high risk of death with a favorable risk/benefit profile for DrotAA treatment. Patients without overt DIC also received significant treatment benefit.