Background: Although Atezo-Bev is the standard of care front line therapy for patients with unresectable HCC, a clinically relevant proportion of patients do not respond, underscoring the need to identify patients most likely to benefit from this therapy. Systemic inflammation is a key risk factor for HCC tumorigenesis and progression and has been associated with poor clinical outcomes. We aimed to evaluate the prognostic value of the inflammatory markers, NLR and PLR, in patients with HCC treated with Atezo-Bev. These markers also have the advantage of being readily available in routine practice and inexpensive. Methods: The association of NLR and PLR with overall survival (OS) was analyzed using a retrospective database of patients with unresectable HCC treated with Atezo-Bev at 14 institutions across the United States, Europe, and Asia from 2019 to 2022. The effect of NLR and PLR on progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) was also assessed. Outcomes of patients with NLR ≥ 5 vs. NLR < 5 and PLR ≥ 300 vs. PLR < 300 were compared. Univariable and multivariable logistic regression models were used to evaluate associations, and survival analyses were performed using the Kaplan-Meier method. Results: The cohort consisted of 296 patients, with a median age of 66 years. The majority of the patients were male (83%), cirrhotic (75%), and had a viral etiology of HCC (66%). All included patients had Child Pugh class A liver disease and good performance status with ECOG score either 0 (47%) or 1 (53%). After a median follow-up of 9.93 months, patients with NLR ≥ 5 had a shorter OS compared to patients with NLR < 5 in univariate analysis (hazard ratio [HR] 2.71, 95% CI 1.71-4.27, P< 0.001), and in multivariate analysis, NLR ≥ 5 remained an independent prognosticator of worse OS (HR 2.01, 95% CI 1.22-3.56, P = 0.007). PLR ≥ 300, compared to PLR < 300, was also associated with shorter OS (HR 2.24, 95% CI 1.71-4.27, P = 0.007) in univariate analysis but not in multivariate analysis (HR 1.01, 95% CI 0.52-1.96, P = 0.99). Both NLR ≥ 5 and PLR ≥ 300 were correlated with shorter PFS on univariate analysis (HR 1.54, 95% CI 1.05-2.25, P = 0.03; HR 1.72, 95% CI 1.04-2.83, P = 0.04; respectively) but not in multivariate analysis (HR 1.31, 95% CI 0.84-2.04, P = 0.24; HR 1.18, 95% CI 0.65-2.13, P = 0.59; respectively). NLR ≥ 5 and NLR < 5 did not differ in ORR (24% vs. 32%, P = 0.39) or DCR (71% vs. 79%, P = 0.24). No differences were observed between patients with PLR ≥ 300 vs. patients with PLR < 300 in ORR (33% vs. 30%, P = 0.81) or DCR (62% vs. 70%, P = 0.09). Conclusions: NLR ≥ 5 was an independent prognosticator of worse OS in patients with unresectable HCC treated with Atezo-Bev and is a prognostic marker worthy of further study and validation.