BACKGROUND: The IMbrave 150 trial revealed that atezolizumab plus bevacizumab (atezo-bev) improves survival in patients with unresectable hepatocellular carcinoma (HCC) (1 year survival rate: 67.2% vs. 54.6%). We assessed the cost-effectiveness of atezo-bev vs. sorafenib as first-line therapy in patients with unresectable HCC from the US payer perspective. METHODS: Using data from the IMbrave 150, we developed a Markov model to compare the lifetime cost and efficacy of atezo-bev as first-line systemic therapy in HCC with those of sorafenib. The main outcomes were life-years, quality-adjusted life-years (QALYs), lifetime costs, and incremental cost-effectiveness ratio (ICER). RESULTS: Atezo-bev demonstrated a gain of 0.44 QALYs, with an additional cost of USD 79,074. The ICER of atezo-bev was USD 179,729 per QALY when compared with sorafenib. The model was most sensitive to the overall survival hazard ratio and body weight. If we assumed that all patients at the end of the IMbrave 150 trial were cured of HCC, atezo-bev was cost-effective (ICER USD 53,854 per QALY). However, if all patients followed the Surveillance, Epidemiology, and End Results data, the ICER of atezo-bev was USD 385,857 per QALY. Reducing the price of atezo-bev by 20% and 29% would satisfy the USD 150,000/QALY and 100,000/QALY willingness-to-pay threshold. Moreover, capping the duration of therapy to ≤12 months or reducing the dosage of bev to ≤10 mg/kg would render atezo-bev cost-effective. CONCLUSIONS: The long-term effectiveness of atezo-bev is a critical but uncertain determinant of its cost-effectiveness. Price reduction would favorably influence cost-effectiveness, even if long-term clinical outcomes were modest. Further studies to optimize the duration and dosage of therapy are warranted.