ImportanceGiven the burden of chronic liver disease on the health care system, more information on the hepatoprotective association of statins in the general population is needed.ObjectiveTo examine whether regular statin use is associated with a reduction in liver disease, particularly hepatocellular carcinoma (HCC) and liver-related deaths, in the general population.Design, Setting, and ParticipantsThis cohort study used data from the UK Biobank (UKB) (individuals aged 37-73 years) collected from baseline (2006-2010) to the end of follow-up in May 2021, from the TriNetX cohort (individuals aged 18-90 years) enrolled from baseline (2011-2020) until end of follow-up in September 2022, and from the Penn Medicine Biobank (PMBB) (individuals aged 18-102 years) with ongoing enrollment starting in 2013 to the end of follow-up in December 2020. Individuals were matched using propensity score matching according to the following criteria: age, sex, body mass index, ethnicity, diabetes with or without insulin or biguanide use, hypertension, ischemic heart disease, dyslipidemia, aspirin use, and number of medications taken (UKB only). Data analysis was performed from April 2021 to April 2023.ExposureRegular statin use.Main Outcomes and MeasuresPrimary outcomes were liver disease and HCC development as well as liver-associated death.ResultsA total of 1 785 491 individuals were evaluated after matching (aged 55 to 61 years on average, up to 56% men, and up to 49% women). A total of 581 cases of liver-associated death, 472 cases of incident HCC, and 98 497 new liver diseases were registered during the follow-up period. Individuals were aged 55-61 years on average, with a slightly higher proportion of men (up to 56%). In UKB individuals (n = 205 057) without previously diagnosed liver disease, statin users (n = 56 109) had a 15% lower hazard ratio (HR) for the association of developing a new liver disease (HR, 0.85; 95% CI, 0.78-0.92; P < .001). In addition, statin users demonstrated a 28% lower HR for the association with liver-related death (HR, 0.72; 95% CI, 0.59-0.88; P = .001) and a 42% lower HR for the development of HCC (HR, 0.58; 95% CI, 0.35-0.96; P = .04). In TriNetX individuals (n = 1 568 794), the HR for the association of HCC was reduced even further for statin users (HR, 0.26; 95% CI, 0.22-0.31; P = .003). The hepatoprotective association of statins was time and dose dependent, with a significant association in PMBB individuals (n = 11 640) for incident liver diseases after 1 year of statin use (HR, 0.76; 95% CI, 0.59-0.98; P = .03). Taking statins was particularly beneficial in men, individuals with diabetes, and individuals with a high Fibrosis-4 index at baseline. Carriers of the heterozygous minor allele of PNPLA3 rs738409 benefited from statin use and had a 69% lower HR for the association with HCC (UKB HR, 0.31; 95% CI, 0.11-0.85; P = .02).Conclusions and RelevanceThis cohort study indicates substantial preventive associations of statins against liver disease, with an association with duration and dose of intake.