['Several cross-sectional studies have shown an association between pre-S mutation and hepatocellular carcinoma (HCC).', 'We aim to verify whether pre-S mutation represents a risk for HCC development in a longitudinal way.', 'A total of 195 patients with chronic HBV infection [age: 43.7\xa0±\xa010.8\xa0years, males: 141 (72.3\xa0%), genotype C: 195 (100\xa0%), hepatitis B e antigen (HBeAg) positive: 109 (55.9\xa0%), cirrhosis: 79 (40.5\xa0%), and pre-S mutation positive: 44 (22.6\xa0%)] were followed up for a median of 7.2\xa0years (range 1.0-7.8\xa0years).', 'HCC developed in 24 patients during follow-up. The 1-, 3-, and 5-year cumulative incidences of HCC were 0.5, 4.9, and 10.4\xa0%, respectively. Patients with pre-S mutation had significantly higher 5-year cumulative incidences of HCC than those without (26.5 vs. 5.7\xa0%, p\xa0<\xa00.001) and showed higher hazard ratio for HCC [3.04 (95\xa0% CI 1.24-7.42), p\xa0=\xa00.015, adjusted for age, gender, HBeAg, cirrhosis and baseline HBV DNA level]. Notably, in patients aged ≥50\xa0years, the 5-year cumulative incidences of HCC in patients with pre-S mutation were considerably high (58.3\xa0%), compared to those without (16.1\xa0%, p\xa0<\xa00.001).'] Is pre-s mutation a significant risk factor for hepatocellular carcinoma development : a long-term retrospective cohort study?