Background: Immune checkpoint inhibitor (ICI) based therapy has emerged as a therapeutic option in hepatocellular carcinoma (HCC), both in combination (IC-C) and as single agent (IC-SA). Approvals were based on clinical trials with strict eligibility criteria limiting generalizability to the entire spectrum of clinical practice. Survival outcomes have not been evaluated in a real-world population and there is no established post ICI treatment standard. Methods: Patients (pts) with advanced HCC treated with ICI across lines of therapy were included in this retrospective study. Data regarding demographics, comorbidities, HCC etiology, liver function (Child Pugh Score [CPS] and ALBI Grade [G]), tumor burden, AFP, treatments, reason for discontinuation (dc) and outcomes were collected. Descriptive statistics and survival analysis were performed using Stata with cox regression analysis. Results: The cohort consisted of 138 pts: median age 63 years (24,95); 83% male; 38% Hispanic/Latino, 27% Asian, 17% Non-Hispanic White, 4% Black and 14% other/unknown. Etiology of cirrhosis: 16% Hepatitis B, 38% Hepatitis C, 12% alcohol liver disease, 9% NAFLD and 24 % mixed/other; Baseline CPS were 74% CPA, 23% CPB, and 2% CPC; ALBI Scores were G1 in 35%, G2 in 53%, and G3 in 12% pts; 62% had extrahepatic disease and/or portal invasion; AFP was ≥ 400ng/mL in 30% of pts. 88% of pts had prior local therapy. For the entire cohort, first line systemic therapy consisted of 52% ICI (18% IC-C and 34% IC-SA) and 48% TKI. mOS was 12 months (mo) (0,74) for first line ICI group and 19.5 mo (3,78) in those with first line TKI. In CPA pts, first line therapy was 51% ICI (24% IC-C and 27% IC-SA) and 39% TKI. 79% of CPA patients received ≥ 2 lines of therapy with second line consisting of 65% ICI and 20% TKI. First line therapy for pts with CPB cirrhosis was 58% ICI (2% IC-C and 55% IC-SA) and 42% TKI. 55% of CPB patients received ≥ 2 lines of therapy and second line therapy for CPB pts included 71% ICI and 18% TKI. mOS was 18 mo in CPA pts and 10 mo in CPB pts. Cirrhosis related complications resulted in treatment discontinuation in 2% of CPA pts vs. 14% of CPB pts. On multivariable analysis, Asian ethnicity (HR 0.41 p = 0.006), CPS (HR 1.64 p = 0.027), and number of treatment lines (HR 0.74 p = 0.005) were associated with OS. Conclusions: This single institution real-world cohort highlights the reality of sequential therapy in pts with advanced HCC. Survival outcomes in our CPA cohort are comparable to data from recent phase 3 trials. The survival in our CPB cohort in a tertiary care setting compares favorably with available data from clinical trials and suggests the feasibility of sequential and effective anti-cancer therapy in this population. Liver function, Asian ethnicity, and number of treatment lines are independent predictors of OS in this cohort of HCC patients receiving ICI. Prospective studies related to optimal treatment sequence and to CPB pts are needed.