Objective To detect the levels of peripheral blood high mobility group box 1 (HMGB1) and procalcitonin (PCT) in patients with septic shock, and analyze their relationship with the severity and prognosis of the disease. Methods 72 patients with septic shock admitted to the intensive care unit of the hospital were selected as the research subjects from March 2017 to March 2021. Peripheral blood samples were collected form the patients to test the levels of HMGB1 and PCT by enzyme-linked immunosorbent assay. The relationship between the levels and the Acute Physiological and Chronic Health Evaluation Ⅱ (APACHEⅡ) score was analyzed. According to 28-day survival, the patients were divided into death group and survival group. Multivariate regression analysis was performed to screen the prognostic factors in patients with septic shock. Results The peripheral blood HMGB1 level was positively correlated with APACHEⅡ score in patients with septic shock (r=0.275, P=0.019), and PCT was positively correlated with APACHEⅡ score (r=0.469, P=0.000). HMGB1 and PCT in the survival group were significantly lower than those in the death group (P<0.05). Logistic regression analysis showed that HMGB1, PCT, age, APACHEⅡ score, and serum albumin were risk factors for poor prognosis of patients with septic shock (P<0.05). The plasma albumin level was negatively correlated with HMGB1 and PCT (r=0.398, r= 0.274, P<0.05). Conclusion Peripheral blood HMGB1 and PCT levels in patients with septic shock are not only closely related to the severity of the disease, but also independent risk factors for death of such patients.