Alcohol-associated liver disease (ALD) is a leading cause of liver-related morbidity, with genetic factors modulating its progression. This study investigates the association of ADH2 polymorphisms with ALD susceptibility and severity, aiming to evaluate their prognostic potential in chronic alcohol users. A case-control study was conducted at Vinayaka Mission’s Medical College, Karaikal, India, from July2022 to July2024, enrolling 60 male participants: 30 ALD cases and 30 controls with alcohol use but no liver disease. ADH2 genotypes were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Severity was assessed via the Child-Pugh score, and alcohol abuse potential and addiction was evaluated with the Alcohol Use Disorders Identification Test (AUDIT). Statistical analyses included chi-square tests, t-tests, and correlation analyses using SPSS version 25.0. The ADH2 × 2 allele was significantly more prevalent in cases (53.3%) than controls (16.7%) (p =.001), correlating with higher Child-Pugh scores (p =.008), ascites (p =.012), and hepatic encephalopathy (p =.025). Cases exhibited elevated AUDIT scores (25.3 ± 8.1 vs. 18.7 ± 6.4, p =.002) and total bilirubin (5.8 ± 3.2 vs. 0.5 ± 0.3 mg/dL, p <.001). ADH2 × 2 polymorphisms are strongly associated with ALD severity, suggesting their utility as a prognostic marker for personalized risk assessment in chronic drinkers. © 2025 Elsevier B.V., All rights reserved.