Simple SummaryHeart failure is a major public health challenge with similar risk factors to those of cancer. HMG-CoA reductase inhibitors, also known as statins, are widely prescribed lipid-lowering agents. Chemoprevention has been reported as a pleiotropic effect of statins. We aimed to evaluate the chemoprotective effect of statins on liver cancer in patients with heart failure and to further identify the differences in effectiveness among statin doses and types. The results demonstrated that statins potentially decreased the risk of liver cancer in patients with heart failure in the entire cohort as well as in sex-, age-, and dose-stratified subgroup analyses as compared with the control group. Moreover, both hydrophilic and lipophilic statins showed significant risk reductions. The findings of the present study demonstrate a potential benefit in terms of liver cancer risk for patients with heart failure using statins.AbstractHeart failure (HF) and cancer have similar risk factors. HMG-CoA reductase inhibitors, also known as statins, are chemoprotective agents against carcinogenesis. We aimed to evaluate the chemoprotective effects of statins against liver cancer in patients with HF. This cohort study enrolled patients with HF aged ≥20 years between 1 January 2001 and 31 December 2012 from the National Health Insurance Research Database in Taiwan. Each patient was followed to assess liver cancer risk. A total of 25,853 patients with HF were followed for a 12-year period; 7364 patients used statins and 18,489 did not. The liver cancer risk decreased in statin users versus non-users (adjusted hazard ratio (aHR) = 0.26, 95% confidence interval (CI): 0.20–0.33) in the entire cohort in the multivariate regression analysis. In addition, both lipophilic and hydrophilic statins reduced the liver cancer risk in patients with HF (aHR 0.34, 95% CI: 0.26–0.44 and aHR 0.42, 95% CI: 0.28–0.54, respectively). In the sensitivity analysis, statin users in all dose-stratified subgroups had a reduced liver cancer risk regardless of age, sex, comorbidity, or other concomitant drug use. In conclusion, statins may decrease liver cancer risk in patients with HF.