Background: Hepatocellular carcinoma (HCC) is the most rapidly growing cause of cancer-related mortality in the United States. Recent preclinical studies suggest that immunotherapy agents targeted at programmed cell death protein 1 (PD-1) do not lead to tumor regression in HCC with underlying nonalcoholic steatohepatitis (NASH). However, further clinical studies are needed to clarify the impact of immunotherapy on patients with NASH-related HCC. Methods: This was a single center, retrospective study analyzing the best responses to immunotherapy in patients with HCC and underlying cirrhosis due to NASH. Patients were divided into 2 groups: those with HCC related to NASH cirrhosis and those with HCC without NASH cirrhosis. All patients received immunotherapy, either as a single agent or in combination with other cancer-directed therapy, with response assessments conducted during their treatment courses. Results: A total of 79 patients were included in this study. There were 15 patients in the NASH cirrhosis-related HCC group and 64 patients in the HCC group without NASH cirrhosis. When analyzing the best disease responses to immunotherapy, 7 patients (46.7%) with HCC and NASH cirrhosis were found to have disease progression as their best responses compared to 7 patients (10.9%) who had HCC without NASH cirrhosis (risk ratio 4.27, p = 0.004). In addition, for the group without NASH cirrhosis, 57 patients (89.1%) experienced disease control (stable disease, partial response, or complete response) from immunotherapy versus 8 patients (53.3%) in the NASH cirrhosis-related HCC group (risk ratio 1.67, p = 0.004). There were no notable differences in patient age, gender, or immunotherapy agents received between the two groups, but there was a significantly greater proportion of patients of Hispanic ethnicity in the HCC group with NASH cirrhosis (p = 0.006, full patient characteristics listed in the table). However, when looking at all individuals in the study, patients of Hispanic ethnicity were not found to have a significantly higher risk of disease progression compared to non-Hispanic patients (p = 0.07). Conclusions: There were significantly higher rates of disease progression as the best response to immunotherapy in patients with HCC and NASH cirrhosis compared to those without NASH cirrhosis. With the expanded use of immunotherapy in HCC patients, further prospective studies are needed to clarify the impact of underlying liver disease etiology on immunotherapy response.