INTRODUCTION: Hepatocellular carcinoma (HCC) is the 4th leading cause of cancer-related mortality worldwide. In US, HCC incidence rates increased by 2–3% annually between 2007 and 2016. The annual cost estimate of HCC is 437$ million/year. It was suggested that aspirin’s (ASA) anti-inflammatory effect might prevent hepatic carcinogenesis. In recent Swedish cohort study, over 50.000 patients with chronic HBV and HCV were followed over 8 yrs. ASA use was associated with significantly lower risk of HCC (4% in ASA users vs 8.3% in non-users OR 0.69; 95% CI 0.62 to 0.76). Given the accelerating incidence and financial burden of HCC in the US, the potential protective effect of ASA in HCC is needed to be examined in US based population. METHODS: We reviewed data from a large commercial database (Explorys IBM) that aggregates electronic health records from 26 nationwide healthcare systems. Using systemized nomenclature of clinical medical terms (SNOMED CT), we identified adults with HCC from 1999 to 2020. HCC risk factors such as chronic HBV, HCV, alcohol abuse, gender, Asian descent, tobacco smoking and non-alcoholic steatohepatitis data were collected. Univariable and multivariable logistic regression analyses were performed to investigate whether ASA use modified the risk of HCC in patients with chronic viral hepatitis. RESULTS: Out of 61.4 million adult patients in the database, 20,630 (0.03%) had documented HCC. Patients were found to have higher prevalence of HCC if they had HCV (2.14% vs 0.02% , OR 115.21, 95% CI: 112.06–118.44), HBV (1.35% vs 0.03% %, OR 44.24, 95% CI: 42.00–46.62), alcohol abuse (0.32% vs 0.03%, OR 11.31 95% CI: 10.90–11.75), male gender (0.05% vs 0.02 %, OR 3.02, 95% CI: 2.93–3.11), Asian race (0.05 % vs 0.03 % OR 1.56 95% CI: 1.43–1.67) and tobacco smoking (0.11% vs 0.02% %, OR 4.49, 95% CI: 4.36–4.62). In Multivariable model, the prevalence ASA use modified the association between prevalence of HCC and HBV or HCV after adjustment for other risk factors. If patient was not on ASA, adjusted odds of prevalence of HCC was much higher (OR 111.35, 95% CI: 107.16–115.70). Whereas, if patient was on ASA with hepatitis B or C infection, this mitigates the prevalence of HCC during that period (OR 28.61, 95% CI: 27.35–29.94). This interaction was statistically significant. CONCLUSION: ASA has possibly a protective role in developing HCC in patients with chronic HBV or HCV. This finding supports the need for randomized controlled trials to test the utility of ASA for primary prevention of HCC.Figure 1.: ASA effect on HCC in chronic viral hepatitis.Table 1.: Multivariate analysis for HCC risk factorsTable 2.: Characteristics of Patients in Cohort