Objective To study the relation of ulinastatin administration (dose and course) with the prognoses of patients with severe sepsis. Methods We retrospectively analyzed the clinical data of selected patients with sepsis, who were treated in the ICU of Changzheng Hospital from January 2010 to April 2014. The blood routine examination, C-reactire protein (CRP), bilirubin, procalcitonin (PCT), and coagulation function were collected within 24 hours after hospitalization, and APACHE Ⅱ was calculated. The patients were grouped into ulinastatin group or the control group. The survival rates were compared between the two groups, and the relationship between ulinastatin (dose/course) and death rate was discussed. Results A total of 134 patients were included, with a mean age of (53.8±17.2) years old. Thirty-six patients (26.9%)died. Thirty-nine patients used ulinastatin; the death rates in the ulinastatin group and the control group were 33.3%(13/39)and 24.2%(23/95), respectively, showing no significant difference(P>0.05). The death rates of the patients with APACHE Ⅱ≥25 were 44.4% (4/9)in the ulinastatin group and 90.0%(9/10) in the control group, showing significant difference (P<0.05). The total dose of ulinastatin was (6.984 6±2.535 7) million unit in the death group and (10.303 8±6.331 9) million unit in the survival group, and the application course was (7.54±3.02) days vs (14.57±6.14) days, both showing significant differences (P<0.05 or P<0.01). Conclusion Megadosing ulinastatin at an early stage can improve the prognosis of sepsis patients with APACHEⅡ≥25.