Aims: Aspirin therapy has been shown to be associated with reduced risk of developing hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). We aimed to investigate the association between aspirin use and HCC risk in CHB patients with or without cirrhosis. Methods: We identified 329,635 adult patients with CHB who underwent health examinations from 2007 through 2017, using the Korean National Health Insurance Service database. Patients who received aspirin for 90 or more consecutive days (n=20,200) and patients who never received antiplatelet therapy (n=309,435) were identified. We generated propensity score-matched cohort to balance baseline characteristics between aspirin users and nonusers. The risk of HCC development was estimated, accounting for death as a competing event. Results: In overall population, propensity score matching analysis generated 19,003 pairs with a median follow-up period of 6.7 years. The cumulative HCC incidence among aspirin users was significantly lower than that among nonusers of aspirin (P<0.0001; panel A). Aspirin use showed a significant association with lower risk of HCC (adjusted hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.78-0.92; P<0.0001). Among patients without cirrhosis (16,507 pairs), aspirin users had significantly lower cumulative incidence of HCC (P<0.0001; panel B) and adjusted HR of 0.87 for HCC (95% CI, 0.79-0.95; P=0.002) compared to aspirin nonusers. However, among patients with cirrhosis (2,479 pairs), the cumulative HCC incidence did not differ significantly between aspirin users and nonusers (P=0.51; panel C) and the association between aspirin therapy and HCC risk was not evident (adjusted HR, 1.0; 95% CI, 0.85-1.18; P=0.99). Cirrhosis had a significant effect on the association between use of aspirin and HCC risk (P<0.0001 for interaction). Conclusions: In this Korean nationwide cohort study of patients with CHB, aspirin therapy was associated with reduced risk of HCC. Cirrhosis had a substantial effect on this association.