Background: Acute cholangitis is associated with high mortality, necessitating prompt diagnosis and intervention. The Tokyo Guidelines 2018 (TG18) are a crucial diagnostic tool, but their sensitivity and specificity require evaluation. Moreover, factors influencing acute cholangitis mortality in Indonesia remain unidentified. This study evaluates the diagnostic accuracy of TG18 and identifies mortality predictors in adult patients with acute cholangitis in Indonesia. Methods: A retrospective cohort study was conducted using the medical records of acute cholangitis patients at Cipto Mangunkusumo Hospital from 2019 to 2022. TG18 was compared with endoscopic retrograde cholangiopancreatography (ERCP). Bivariate and multivariate analyses were employed to identify mortality predictors. Results: The study involved 163 individuals (male: 51.5%; mean age: 51.0 ± 12.81 years). The in-hospital mortality rate was 11.6%. TG18 demonstrated a sensitivity and specificity of 84.05% (95% confidence interval (CI):77.51%–89.31%) and 95.65% (95%CI: 78.05%–99.89%), respectively, compared with ERCP. Significant mortality predictors in univariate analysis included TG18 grade III (risk ratio (RR): 13.85; 95%CI: 3.31–57.89; p<0.001), history of malignancy (RR: 4.40; 95%CI: 1.52–12.68; p=0.006), noncompliance with antibiotic guidelines (RR: 3.27; 95%CI: 1.36–7.85; p=0.008), and procalcitonin levels ≥ 2.0 ng/dL (RR: 2.44; 95%CI: 1.056–5.63; p=0.037). Multivariate analysis revealed that significant predictors included TG18 grade III (RR: 10.67; 95%CI: 2.50–45.56; p<0.001), non-compliance with antibiotic guidelines (RR: 2.92; 95%CI: 1.34–6.36; p=0.007), and procalcitonin levels ≥ 2.0 ng/dL (RR: 2.37; 95%CI: 1.18–4.75; p=0.015). Conclusion: TG18 demonstrates favorable sensitivity for diagnosing acute cholangitis. Independent predictors of acute cholangitis mortality include TG18 grade III, noncompliance with antibiotic guidelines, and procalcitonin levels ≥ 2.0 ng/dL. © 2025, Indonesian Society of Internal Medicine. All rights reserved.