Abstract: Objective Clostridium difficile was a major factor leading to poor prognosis and prolonged hospital stay in critically ill patients. The present study was to investigate the clinical features of Clostridium difficile infection in patients with septic shock. Methods From January, 2015 to December, 2016, 218 consecutive cases of patients with septic shock in our hospital were collected. According to the development of Clostridium difficile infection or not, all patients were assigned into an infection group (n=56) or a control group (n=162). The clinical features of the both groups were compared. Results Compared with the control group, patients in the infection group got higher rates of APPACHEⅡ ≥ 20 (57.14% vs. 31.48%, P=0.001), lactate ≥ 4 mmol/L (67.86% vs. 46.91%, P=0.007), acute kidney injury (71.43% vs. 46.30%, P=0.001), acute lung injury (75.00% vs. 54.32%, P=0.007), multiple organ failure (51.79% vs. 30.86%, P=0.005), antibiotics usage ≥ 14 days (60.71% vs. 41.98%, P=0.015), proton pump inhibitor ≥ 14 days (60.71% vs. 44.44%, P=0.036), vasoactive drugs ≥ 7 days (41.07% vs. 25.93%, P=0.033), mechanical ventilation (62.50% vs. 40.74%, P=0.005) and hemofiltration (50.00% vs. 34.57%, P=0.041). Multivariate logistics regression analysis revealed that APPACHE score ≥ 2 0 and lung failure were risk factors for Clostridium difficile infection in septic shock patients (P<0.05). Conclusion APPACHE score ≥ 20 and lung failure were risk factors for Clostridium difficile infection in septic shock patients. Intensive care and prevention should be taken to reduce the infection rate of Clostridium difficile in these critically ill patients.