Background: Hepatocellular carcinoma (HCC) is the fastest-growing cancer in the US with more age-adjusted incident cases in Hispanics compared to non-Hispanics. Immunotherapies are considered integral part of treatment for most unresectable HCC. Recent multinational phase III trials suggest the benefit of immunotherapies may differ based on geographic region and underlying etiology of HCC. We hypothesized that Hispanic ethnicity might influence responses to immunotherapy in HCC. Methods: We analyzed the National Cancer Database (NCDB) to assess the impact of immunotherapy on overall survival (OS) in Hispanic patients with HCC. The database was queried for liver cancer from 2004 to 2020. Kaplan Meier method was used to assess OS and a log-rank test was used to compare survival distribution between Hispanic and non-Hispanic groups. Cox regression analysis was performed to estimate the adjusted effect of ethnicity on OS based on immunotherapy status. NCDB is a joint project of the Commission on Cancer (CoC) of the American College of Surgeons and the American Cancer Society. The CoC's NCDB and the hospitals participating in the CoCÕs NCDB are the source of the de-identified data used herein. Results: A total of 225079 patients were identified of whom 2036 patients (0.9%) received immunotherapy as first-line treatment. Patients with non-Hispanic ethnicity, male sex, who received treatment at academic/research institutions, and were insured were more likely to receive immunotherapy. In the entire cohort, there was no difference (p=0.94) in survival between those who did not receive immunotherapy (median OS,11.63 months; IQR: 2.79, 34.83) vs. those who did (median OS, 10.68 months, IQR: 5.19, 23.29[DA2]). There were more Hispanics in the cohort who did not receive immunotherapy (12.28% vs. 10.61%). In the adjusted Cox analysis, Hispanics had a reduced risk of death than non-Hispanics among patients who did not receive immunotherapy (HR: 0.873, 95%CI, 0.858-0.889; p<0.001). Among patients with immunotherapy, there was no OS difference between ethnicities (HR 0.904, 95% CI, 0.755-1.082; p 0.271). Conclusions: Hispanics were less likely to receive immunotherapy than non-Hispanics. Although Hispanics had a better OS than non-Hispanics among patients without immunotherapy, the differences no longer persist among patients who received immunotherapy. These findings suggest that Hispanic ethnicity may influence responses to immunotherapy. As compared to non-Hispanic whites, Hispanics with HCC have significantly more nonalcoholic fatty liver disease and alcohol-related liver disease as contributing factors. A better understanding of the impact of immunotherapies on alcoholic and nonalcoholic liver disease-related HCC is needed.