Background and aims Anti-neoplastic immunotherapy has revolutionized cancer management; however, its safety profile with respect to liver-related injury remains largely unexplored. Herein, we analyzed a United States national database to determine the incidence, mortality, and predictors of hepatotoxicity in the setting of anti-neoplastic immunotherapy. Methods This was a nationwide retrospective study of hospital encounters from 2011 to 2014 using the National Inpatient Sample (NIS) database. We utilized the International Classification of Diseases, Ninth Revision (ICD-9) coding system to identify all adult patients who underwent anti-neoplastic immunotherapy during hospitalization. The primary outcome was the incidence of hepatotoxicity during the same hospitalization. Secondary outcomes included in-hospital mortality as well as socioeconomic and ethno-racial predictors of hepatotoxicity. Analyses were performed using IBM SPSS Statistics 23.0. Results The sample included 3002 patients who underwent inpatient anti-neoplastic immunotherapy. The incidence of hepatotoxicity was 10.1%, which was significantly higher as compared to a matched inpatient population (adjusted odds ratio (aOR) 4.93, 95% confidence interval (CI): 3.80–6.40, P = 0.001). No significant mortality difference was seen in those that developed hepatotoxicity compared to those who did not (aOR 0.47, 95% CI: 0.03–8.03, P = 0.612). Age under 60 (aOR 1.56, 95% CI: 1.23–1.78, P = 0.050) and white race (aOR 1.85, 95% CI: 1.35–2.04, P<0.010) were independent risk factors for developing immunotherapy-associated hepatotoxicity. Conclusions In this large, nationwide database analysis, we found that anti-neoplastic immunotherapy was associated with a nearly five-fold risk of in-hospital hepatotoxicity as compared to a matched inpatient population, though without an associated mortality difference. Additionally, younger age and white race were identified as predictors of immunotherapy-associated hepatotoxicity. Heightened vigilance and prospective investigation of the risk factors and liver-related adverse effects of anti-neoplastic immunotherapy are warranted.