Simple SummaryThe impacts of daily low-dose aspirin on hepatoma occurrence and gastrointestinal bleeding incidence in cirrhotic patients remain unknown. This retrospective study enrolled 66,984 cirrhotic patients with laboratory data, the largest cirrhotic cohort. Aspirin users, but not those of other antiplatelet agents, showed a dose-dependent reduction in hepatoma incidence and overall mortality. Daily aspirin did not increase the gastrointestinal bleeding incidence rate in cirrhotic patients.AbstractBackground: Cirrhosis is the primary risk factor for hepatocellular carcinoma (HCC) and gastrointestinal bleeding (GI). We aimed to assess the efficacy and safety of daily aspirin on HCC occurrence, overall survival, and GI bleeding in cirrhotic patients. Methods: A total of 35,898 eligible cases were enrolled for analyses from an initial 40,603 cirrhotic patients without tumor history. Patients continuously treated with aspirin for at least 84 days were in the therapy group, whereas those without treatment were controls. A 1:2 propensity score matching by age, sex, comorbidities, drugs, and significant clinical laboratory tests with covariate assessment was used. Results: Multivariable regression analyses revealed that daily aspirin use was independently associated with a reduced risk of HCC (three-year HR 0.57; 95% CI 0.37–0.87;p= 0.0091; five-year HR 0.63, 95% CI 0.45–0.88;p= 0.0072) inversely correlated with the treatment duration [3–12 months: HR 0.88 (95% CI 0.58–1.34); 12–36 months: HR 0.56 (0.31–0.99); and ≥ 36 months: HR 0.37 (0.18–0.76)]. Overall mortality rates were significantly lower among aspirin users compared with untreated controls [three-year HR 0.43 (0.33–0.57); five-year HR 0.51 (0.42–0.63)]. Consistent results were obtained when the laboratory data were included in the propensity score for matching. Conclusions: Long-term aspirin use significantly reduced the incidence of HCC and overall mortality without increasing gastrointestinal bleeding in cirrhotic patients.