Background <p>This study aims to elucidate the association between estimated plasma volume status (ePVS) trajectory changes and intensive care unit (ICU) mortality.</p> Methods <p>Data were extracted from the MIMIC-IV (version 3.1) database from 2008 to 2022. Patients aged 18 to 80 years who met the Sepsis-3 criteria were included. Patients who were not in their first hospital admission or first ICU stay, had an ICU stay shorter than 7 days or longer than 100 days, or lacked sufficient hemoglobin or hematocrit data to calculate ePVS at the required time points were excluded. Group-based trajectory modeling (GBTM) was used to identify distinct ePVS trajectories. Kaplan-Meier survival curves and Cox proportional hazards models were used to compare ICU mortality across ePVS trajectory groups. Restricted cubic splines (RCS) were used to analyze the dose-response relationship between Day 1 ePVS and outcomes.</p> Results <p>Among 5208 patients with sepsis, three distinct ePVS trajectories were identified, namely Trajectory 1 (low-ascend), Trajectory 2 (medium-ascend), Trajectory 3 (high-ascend). Kaplan–Meier analysis showed Trajectory 1 having the highest survival probability among the ePVS trajectories. After multivariable adjustment, Trajectory 3 remained significantly associated with a higher risk of ICU mortality compared with Trajectory 1, with a hazard ratio (HR) of 1.20 (95%CI 1.01–1.44, <i>p</i> = 0.039). RCS analysis showed a significant linear association between Day 1 ePVS and ICU mortality. Subgroup analyses showed generally consistent results, and no significant interactions were detected.</p> Conclusion <p>Distinct ePVS trajectories were associated with ICU mortality in sepsis patients, with the high-ascend trajectory showing the highest mortality risk.</p> Clinical trial <p>Not applicable.</p> Graphical Abstract <p></p>