Background: Despite advances in understanding the molecular pathways of HCC, therapeutic options are limited and patient survival is dismal. IO is a promising HCC treatment and predicted to become first line therapy. Little is known about indicators predicting a prolonged response to IO or the effects of IO on subsequent TKI treatment. Methods: In this single-institutional retrospective analysis, pts received one of five IO containing regimens with nivolumab, pembrolizumab, atezolizumab plus bevacizumab, durvalumab or cemiplimab until disease progression (PD) or unacceptable toxicity. Relevant clinical factors including, but not limited to: stage, viral etiology, vascular invasion, tumor thrombus, multifocal disease, toxicity grade and additional therapies, were correlated to clinical outcome: progression free survival (PFS), overall survival (OS), response rate (RR), using Pearson’s chi-square test or student's t-test. Responses were assessed using RECIST v 1.1 criteria for stable disease (SD), partial response (PR) and PD were correlated with best response and PFS. OS was calculated by the Kaplan-Meier method. Results: Cohort demographics (n = 76) were: 72% male; 38% African American, 30% Caucasian and 16% Asian; 29% of pts had HBV, 41% had HCV, 1% had both HBV/HCV and 13% had no viral etiology (n = 64). The majority of pts were stage III (43%) or IV (38%). Best response to IO was SD in 65.7% of pts, PR in 25.7% and PD in 8.6%. Median OS was 13m (95% CI 7.9-18.1) from the start of IO and median PFS (n = 65) was 14m (95% CI 6.8-21.2). Median OS and PFS were significantly improved in pts with PR compared to PD (45 vs 8m, p < 0.0005, PFS 15 vs 3m p = 0.007). Both OS and PFS showed benefits for SD of ≥2 months compared to those with PD (11 vs 8m, p < .0005, PFS 5 vs 3m p = .007). Abnormal TSH anytime during IO treatment tended toward prolonged mOS (20 vs 9m p = 0.126). Thirty-five pts received additional lines of therapy after IO, 57% (N = 20) received a TKI and 14.2% (N = 5) received additional IO agents. Those who received TKI upon completion of IO had a significantly improved OS (p = 0.014) versus those who did not; median OS 22 m (95%CI 12.7-31.3) versus 10m (95%CI 5.4-14.6). Conclusions: PR and SD are independent predictors for prolonged PFS and OS in HCC pts receiving IO therapy. Abnormal TSH during IO treatment tended toward improved mOS. In addition data strongly indicates subsequent TKI therapy improves patient outcomes after IO.