Sepsis is a serious disease with high clinical morbidity and mortality. Despite the tremendous advances in medicine and nursing, treatment of sepsis remains a huge challenge. Our purpose was to explore the effects of shock index (SI) trajectory changes on the prognosis of patients within 24 h after the diagnosis of sepsis.This study was based on Medical Information Mart for Intensive Care IV (MIMIC- IV). The effects of SI on the prognosis of patients with sepsis were investigated using C-index and restricted cubic spline (RCS). The trajectory of SI in 24 h after sepsis diagnosis was classified by latent growth mixture modeling (LGMM). Cox proportional hazard model, double robust analysis, and subgroup analysis were conducted to investigate the influence of SI trajectory on in-hospital death and secondary outcomes.A total of 19,869 patients were eventually enrolled in this study. C-index showed that SI had a prognostic value independent of Sequential Organ Failure Assessment for patients with sepsis. Moreover, the results of RCS showed that SI was a prognostic risk factor. LGMM divided SI trajectory into seven classes, and patients with sepsis in different classes had notable differences in prognosis. Compared with the SI continuously at a low level of 0.6, the SI continued to be at a level higher than 1.0, and the patients in the class whose initial SI was at a high level of 1.2 and then declined had a worse prognosis. Furthermore, the trajectory of SI had a higher prognostic value than the initial SI.Both initial SI and trajectory of SI were found to be independent factors that affect the prognosis of patients with sepsis. Therefore, in clinical treatment, we should closely monitor the basic vital signs of patients and arrive at appropriate clinical decisions on basis of their change trajectory.Copyright © 2022 Xu, Zhang, Huang, Han, Yang, Zheng, Feng, Huang, Yin and Lyu.