Organ failure (OF) largely governs the outcomes and mortality in patients with acute pancreatitis (AP), but there is a lack of optimal prognostic biomarker for OF. This study is designed to investigate whether the serum apolipoprotein A-I (Apo A-I) level can predict OF in patients with AP.A total of 424 patients with AP were reviewed in the study, and we finally got 228 patients eligible for analysis. Patients were divided into two groups based on serum Apo A-I level. Demographic information and clinical materials were retrospectively collected. The primary outcome was the occurrence of OF. Univariate and multivariate binary logistic regression were conducted to analyze the relationship between Apo A-I and OF. Additionally, we used receiver operating characteristic analysis to clarify the predictive value of serum Apo A-I level for OF and mortality.Ninety-two patients and 136 patients were included in Apo A-I low and non-low groups, respectively. The occurrence of OF was significantly different in the two groups (35.9 vs. 9.6%, p < 0.001). Moreover, serum Apo A-I level markedly decreased across disease severity based on the 2012 Revised Atlanta Classification of AP. The decrease of serum apolipoprotein A-I was an independent risk factor for organ failure (OR: 6.216, 95% CI: 2.610, 14.806, p < 0.001). The area under the curve of serum Apo A-I was 0.828 and 0.889 for OF and mortality of AP, respectively.Serum Apo A-I level in the early stage of the disease has a high predictive value for OF of AP.