OBJECTIVE: To investigate the early dynamic changes of biomarkers associated with capillary leak syndrome (CLS) in patients with severe acute pancreatitis (SAP) and their correlation with multiple organ failure (MOF). METHODS: A total of 171 SAP patients admitted to the West China Centre of Excellence for Pancreatitis, West China Hospital, Sichuan University between September 1, 2019 and December 31, 2020 were enrolled for this study. The patients were divided into MOF and non-MOF groups based on the occurrence of MOF in the first 5 days of hospitalization, and were further divided into subgroups based on the presence of moderate-to-severe intra-abdominal hypertension (IAH). We performed dynamic monitoring of the blood biomarkers (hematocrit [HCT], blood urea nitrogen [BUN], and creatinine [Cr]), plasma proteins (albumin [Alb], total protein [TP], and non-albumin plasma proteins [NAPP]), and intra-abdominal pressure. Trends in these indicators across groups were analyzed comprehensively. RESULTS: No significant differences in baseline data between the two groups were observed. The baseline data of the 2 groups were comparable. The MOF group had significantly higher rates of persistent systemic inflammatory response syndrome (SIRS) lasting 48 hours (91.3% vs. 71.8%), ICU admission (70.4% vs. 17.6%), and length-of-stay ([32 ± 17.7] days vs. [19.0 ± 12.2] days) compared to those of the non-MOF group ( CONCLUSION: The CLS model of SAP patients is validated, confirming that CLS is a key factor in the progression from SIRS to MOF. The loss of NAPP is an early and important indicator of CLS persistence and progression to MOF. Additionally, moderate-to-severe IAH accelerates the deterioration of MOF. These findings provide valuable insights into the potential mechanisms of MOF and warrant further validation through large-scale prospective studies.