Simple SummaryAspirin has been observed to reduce the risk of developing hepatocellular carcinoma (HCC). This review pooled together the results of all available published studies and found that aspirin reduces the risk of HCC by around 30%. In patients with cirrhosis, this effect was not seen and, overall, patients treated with aspirin were at a higher risk of bleeding, as expected. Our findings provide compelling observational evidence for the use of aspirin as a potential preventative treatment for patients at risk of HCC, but highlight the need for further study into the optimal patient group that would benefit, and the need to balance against the risk of bleeding.AbstractAn increasing number of observational studies have described an association between aspirin use and a reduced risk of incident hepatocellular carcinoma. We performed this meta-analysis to provide a comprehensive and updated aggregate assessment of the effect of aspirin on HCC incidence. Two independent authors performed a systematic search of the literature, utilising the Medline, Embase, Scopus, and PubMed databases. A total of 16 studies (12 cohort studies, and 4 case-control studies) were selected for inclusion, with a large number of studies excluded, due to an overlapping study population. The pooled analysis of cohort studies involving a total population of approximately 2.5 million subjects, 822,680 aspirin users, and 20,626 HCC cases demonstrated a 30% reduced risk of HCC associated with aspirin use (adjusted HR 0.70, 95%CI 0.60–0.81). There was a similar but non-significant association observed across the case-control studies (adjusted OR 0.60, 95%CI 0.32–1.15,p= 0.13), which involved a total of 1961 HCC cases. In a subgroup meta-analysis of patients with cirrhosis, the relationship between aspirin use and incident HCC diminished to non-significance (adjusted HR 0.96, 95%CI 0.84–1.09). Aspirin use was associated with a statistically significant increase in bleeding events when all relevant studies were pooled together (adjusted HR 1.11, 95%CI 1.02–1.22). Prospectively collected data should be sought, to define the optimal patient group in which aspirin is safe and effective for the chemoprophylaxis of HCC.