Background: Acute on chronic liver failure (ACLF) is a severe form of liver cell failure with high mortality rates. Hepatocyte cell death in ACLF can occur through necrosis or apoptosis. The M30 fragment of caspase-cleaved cytokeratin 18 is a marker of caspase-mediated apoptosis. Objective: To assess serum caspase-cleaved CK 18 (M30) level as a diagnostic marker for acute-on-chronic liver failure (ACLF) in chronic hepatitis C cirrhosis patients. Furthermore, to determine the optimal cut-off level of serum caspase-cleaved CK 18 (M30) for diagnosing ACLF and its association with ACLF severity. Methods: The study involved 60 chronic HCV cirrhotic patients with ACLF (Group 1), 15 chronic HCV compensated cirrhotic patients (Group 2), and 15 healthy controls (Group 3). Laboratory tests and radiological asse-ssments were conducted, including calculation of Child–Pugh score, MELD score, Consortium Liver Failure-Organ Failure (CLIF-OF) score, and CLIF-C-ACLF score using the EASL calculator. Serum level of caspase-cleaved CK 18 (M30) was measured using ELISA. Results: The serum level of caspase-cleaved CK 18 (M30) was significantly higher in group 1 compared to groups 2 and 3. Serum caspase-cleaved CK 18 (M30) showed a high predictive value for ACLF. At a cut-off level of 3.45 ng/ml, caspase-cleaved CK 18 (M30) had a sensitivity of 85% and specificity of 93.3% and AUC of 0.902 (95% CI = 0.833–0.970). There was a positive correlation between serum caspase-cleaved CK 18 (M30) levels and CLIF-C-ACLF score, indicating its potential as a predictor of ACLF severity. Conclusion: Serum caspase-cleaved CK 18 (M30), at cut off value of 3.45 ng/ml can accurately predict acute-on-chronic liver failure in patients with chronic HCV cirrhosis. Higher levels were associated with increased ACLF severity and mortality.