Abstract: OBJECTIVE To explore the efficacy and safety of hydrocortisone in combination with hydrofluorocortisone in treatment of septic shock in adults, and to provide reference for clinical application. METHODS A study was conducted on patients diagnosed with septic shock in our hospital from Dec.2013 to Dec. 2016. 80 patients were enrolled and randomized into the experimental group and the control group. The 40 patients in the experimental group were treated with hydrocortisone and hydrofluorocortisone, whereas the other 40 patients in the control group received placebo. Mortality, heart index, heart rate, systolic blood pressure, diastolic blood pressure, incidence of adverse reactions, and survival analysis results were recorded for both groups. RESULTS Compared with the control group, patients in the experimental group had a 90-day mortality rate of 15.0% and a 180-day mortality rate of 25.0%, significantly lower than those of the control group (25.0% and 37.5%, respectively) (P<0.05). The improvement of cardiac function in septic shock patients of the experimental group was more significant than in the control group (P<0.05). The survival rate after 1 year was 55.3% in the experimental group, significantly higher than that in the control group (40.2%)(P<0.05). In terms of adverse reactions, the risk of hyperglycemia in the experimental group was significantly higher (P<0.05). CONCLUSION Treatment with hydrocortisone in combination with hydrofluorocortisone can effectively reduce the mortality rate of adult patients with septic shock, but it can lead to an increased risk of hyperglycemia.