Abstract Background: Hepatocellular carcinoma (HCC) is a lethal malignancy that currently ranks fourth in cancer-related deaths in the US and is projected to become the third leading cause of cancer death in the US by 2030. Thus, there is a pressing need to identify modifying risk factors to improve survival after diagnosis of HCC. Statins and metformin are among the most commonly prescribed medications in the elderly in the US and there are experimental data suggesting that these medications may improve overall survival after cancer diagnosis; however, results from observational studies have been equivocal. We therefore investigated the potential benefits of pre- and post-diagnosis use of statins and metformin both independently and jointly on overall survival after diagnosis of HCC. Methods: The study was performed using data from the Surveillance, Epidemiology, and End Results (SEER-18) registry linked to Medicare claims data and included 8,922 elderly (≥65 years) patients diagnosed with HCC between 2009-2013. Data on metformin and statins use were extracted from the Medicare Part D Claims file and the patients were grouped as statins only users, metformin only users, both statins and metformin users, or neither (i.e., non-users, referent group). We assessed association of both pre-diagnosis (≥2 years) and post-diagnosis statins and metformin use on risk of death after diagnosis of HCC. Statins users were further categorized into high potency statins users (simvastatin, atorvastatin, and rosuvastatin) or low potency statins users (pravastatin, lovastatin, and fluvastatin) and compared with non-users. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for multiple risk factors, including age sex, race, cancer stage at diagnosis, cancer grade, first course therapy, neighborhood level education and income, Charlson comorbidity index, and diabetes severity index. Results: Compared with non-users, post-diagnosis statins use was independently associated with 27% lower risk of death after diagnosis of HCC (HR=0.73, 95% CI: 0.60-0.88; p-value = 0.002), adjusting for pre-diagnosis statins use and other risk factors. Further analysis showed that the association for post-diagnosis statins use is evident only among high potency statins users (HR=0.72, 95% CI: 0.60-0.88; users versus non-users) but not low potency statins users (HR=0.83, 95% CI: 0.55-1.25; users versus non-users). No association was found for pre-diagnosis statins use or for pre- or post-diagnosis metformin use. Conclusions: This study suggests that post-diagnosis statins use, particularly high potency statins use, may improve overall survival after diagnosis of HCC. Metformin use, both before and after diagnosis of HCC, is not associated with overall survival. Citation Format: Samuel O. Antwi, Zhuo Li, Kabir Mody, Tushar C. Patel. Independent and joint use of statins and metformin on overall survival after diagnosis of hepatocellular carcinoma: A SEER-Medicare matched study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1192.