Objective To explore the effect of sequential organ failure assessment (SOFA) combined with soluble programmed death factor-1 (sPD-1) level on the prognosis of patients with sepsis. Methods A total of 86 patients with sepsis in our hospital from March 2019 to March 2021 were selected and divided into survival group (59 cases) and death group (27 cases) according to their prognosis (28-day outcome). The levels of sPD-1, inflammatory cytokines, SOFA and APACHEⅡ scores of two groups were recorded. The risk factors of 28-day mortality were analyzed. The prognostic values of SOFA+sPD-1 in patients with sepsis were analyzed by ROC curve. Results Age, C-reactive protein (CRP), procalcitonin (PCT) and sPD-1 levels and SOFA, APACHEⅡ scores of death group were higher than those of survival group (P＜0.05). By Logistic regression analysis, sPD-1 level, SOFA and APACHEⅡ scores were identified as independent predictors of 28-day death in patients with sepsis (P＜0.05). After combining prediction, the area under the ROC curve of SOFA+sPD-1 was the largest (0.862), and the sensitivity and specificity were 88.89% and 88.14% respectively. Conclusion In the prognosis evaluation of patients with sepsis, both sPD-1 level and SOFA score were independent predictors of 28-day mortality, and SOFA+sPD-1 was more effective in predicting the prognosis of patients with sepsis.