Background: Combination PD-(L)1/CTLA-4 blockade is approved in patients with advanced hepatocellular carcinoma (HCC) in the first line or after treatment with sorafenib, but it is unclear if combination therapy has efficacy after treatment with anti-PD-(L)1 alone or in combination with a multikinase inhibitor. We evaluated responses to ipilimumab plus nivolumab in patients with advanced HCC who previously received anti-PD-(L)1 to assess the efficacy and safety of this regimen. Methods: We performed a multi-center retrospective review of patients 18 years of age or older with a diagnosis of HCC based on histology or imaging who had received at least one dose of anti-PD-(L)1 therapy prior to receiving ipilimumab plus nivolumab as a subsequent line of therapy. All patients had imaging and/or laboratory monitoring to monitor for disease progression. Results: Our cohort contained 32 patients, with a majority being male (88%, n = 28) and a median age of 67 years. All patients were Child Pugh A (66%, n = 21) or B (34%, n = 11) at the start of treatment, with most having an ECOG performance status of 0-1 (84%, n = 27). The median number of prior lines of therapy was 2 (range 1-8). Prior anti-PD-(L)1 containing regimens included atezolizumab plus bevacizumab (50%, n = 16), other VEGF plus anti-PD-(L)1 combination (31%, n = 10), and anti-PD-(L)1 monotherapy (19%, n = 6). The objective response rate (ORR) was 22% (1 CR, (3%), 6 PR (19%)), with remaining responses including 8 SD (25%), 16 PD (50%), and 1 NE (3%). Among patients who had an objective response to ipilimumab plus nivolumab, none had an objective response to prior anti-PD-(L)1 treatments. Response rates were similar across major clinical (obese vs. non-obese) and etiological (viral vs. non-viral) subsets of HCC. Response to ipilimumab plus nivolumab was associated with improved PFS and OS: median PFS for PD/SD/NE 2.4 months (95% CI: 2.1-NR) vs. PR/CR not reached (NR) (95% CI: 7.5-NR), p = 0.004, and OS for PD/SD/NE 5.9 months (95% CI: 3.1-NR) vs. PR/CR NR (95% CI: NR-NR), p = 0.02. Immune related adverse events (irAEs) were reported in 13 patients (41%), and 6 patients experienced grade 3-4 irAEs (19%). One patient in our cohort experienced a fatal irAE (autoimmune hepatitis), and 5 patients discontinued therapy due to irAEs. Conclusions: This study demonstrates that ipilimumab plus nivolumab has clinical activity in patients with advanced HCC who previously received anti-PD-(L)1 therapy with an acceptable safety profile, supporting this regimen as second line immune checkpoint inhibitor therapy in advanced HCC. Further studies are required to determine the optimal sequence of therapies in advanced HCC.