Background: Nivolumab plus ipilimumab (NIVOIPI) demonstrated promising efficacy in patients with unresectable hepatocellular carcinoma(uHCC) in the phase 1/2 CheckMate 040 trial. However, as atezolizumab plus bevacizumab (Ate/Bev) is a new first-line standard systemic therapy, it is necessary to evaluate the role of NIVOIPI after treatment with Ate/Bev. Methods: Patients with uHCC who received NIVOIPI after previous systemic treatment were included. Patients received nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) every 3 weeks (four doses), followed by nivolumab (240 mg) every 2 weeks. Patients with Child B/C class and BCLC D stage uHCC were excluded. Patients who had at least one follow-up visit after the start of NIVOIPI were included. Results: A total of 47 patients were included with characteristics as follows: median age of 60 years (range, 37–79); hepatitis B (n = 40, 85.1%), hepatitis C (n = 2, 4.3%), non-viral (n = 5, 10.5%); BCLC B/C (n = 2, 4.3%; n = 45, 95.7%); macrovascular invasion (n = 12, 25.5%); extrahepatic metastasis (n = 41, 87.2%); and AFP ≥ 400 ng/ml (n = 26, 55.3%). Thirty-five (74.5%) patients had a history of prior immune-checkpoint inhibitor (ICI) treatment (n = 35, 74.5%), including Ate/Bev (n = 23, 48.9%). According to the RECIST 1.1, 12 patients achieved a partial response, resulting in an overall response rate (ORR) of 25.5% and disease control rate (DCR) of 42.6%. The ORR and DCR were 41.7% and 58.4% in ICI-naïve patients and 20.0% and 37.1% in patients with prior ICI treatment. The median follow-up duration was 5.7 months (95% confidence interval [CI], 5.4–6.1), the median progression-free survival was 1.4 months (95% CI, 1.1–1.7) in all patients, 1.3 months (95% CI, 0.1–1.1) in prior ICI-treated patients and was not reached in ICI-naïve patients. The median overall survival was not reached. The most common grade 3–4 toxicities were aspartate aminotransferase elevation (n = 4, 8.5%), neutropenia (n = 4, 8.5%), skin toxicity (n = 3, 6.4%), alanine transaminase elevation (n = 2, 4.3%) and pneumonitis (n = 2, 4.3%). There was one treatment-related death due to toxic epidermal necrolysis. Conclusions: NIVOIPI demonstrated clinical meaningful efficacy in patients with uHCC, with and without prior ICI treatment.