Objective To analyze the clinical features of different sepsis phenotypes and their impact on prognosis under the guidance of PiCCO monitoring. Methods A retrospective analysis was performed for the clinical data of patients with sepsis admitted to Department of Intensive Care Medicine from January 2018 to December 2023, and a total of 98 patients were included. All patients were monitored with PiCCO within 1 hour of admission, and the phenotypes were derived by K-means cluster analysis, and the patients were divided into cluster 1 (very low cardiac output sepsis group, n=14), cluster 2 (low cardiac output sepsis group, n=31), and cluster 3 (normal cardiac output sepsis group, n=53). The data of complications, related serum index levels, duration of mechanical ventilation, length of hospitalization, time of vasoactive drugs, and 28-day survival of different hemodynamic sepsis phenotypes were analyzed, and the age, underlying disease, and SOFA score of patients were collected, and their clinical characteristics, prognostic differences, and influencing factors were analyzed. Results Significant differences were observed among the sepsis phenotypes in 28-day survival and the duration of vasoactive agent use. Compared to the normal cardiac output group, the low cardiac output phenotype showed a tendency for prolonged vasoactive agent use, while the extremely low cardiac output phenotype was distinctly associated with significantly increased pulmonary vascular permeability, improved oxygenation, and a markedly lower 28-day survival time. Patients with extremely low cardiac output sepsis suffered a significantly increased early mortality (on days 3 and 5).However, this effect did not persist into the later phase (beyond day 7). Furthermore, the duration of mechanical ventilation was identified as a consistent independent risk factor for mortality, both in the short and long term. Specifically, the pulmonary vascular permeability index (PVPI) and cardiac index (CI) were key determinants of mid-term mortality risk, particularly on days 5 and 7.Conclusion Under the guidance of PiCCO monitoring, different sepsis phenotypes show obvious differences in clinical features and prognosis, which have important guiding value for the selection of clinical treatment strategies