Background: Atezolizumab monotherapy is indicated as 1L treatment for mNSCLC patients with high programmed death ligand-1 (PD-L1) expression (≥ 50%) and without epidermal growth factor receptor or anaplastic lymphoma kinase mutations. This analysis assessed the cost-effectiveness of 1L atezolizumab monotherapy vs. pembrolizumab monotherapy for mNSCLC patients with high PD-L1 expression from a US third-party payer perspective. Methods: A Markov model with progression-free, progressive disease (PD), and death states was developed in Microsoft Excel to compare clinical and cost outcomes of atezolizumab monotherapy vs. pembrolizumab monotherapy. Efficacy, safety, and utility data were derived from systematic reviews and indirect comparisons of the IMpower110, Keynote-024, and Keynote-042 trials. Product prescribing information and clinical trials informed dosing and administration. Wholesale acquisition cost (WAC, accessed in January 2021) for drugs were used while other cost inputs were derived from publicly available fee schedules and peer-reviewed literature. The key outcome of interest was the incremental cost-effectiveness ratio (ICER) expressed as cost per quality-adjusted life-year (QALY) gained. Deterministic sensitivity analysis with 20% variation and probabilistic sensitivity analyses (PSA) were performed to address uncertainties around input parameters. Results: In the base case, 1L atezolizumab monotherapy was projected to increase life expectancy for patients by 0.60 life-years (4.35 vs. 3.75) and 0.47 QALYs (3.46 vs. 2.98) over pembrolizumab monotherapy at an incremental cost of $27,947 (mean total cost: $396,811 vs. $368,864), resulting in an ICER of $58,841/QALY gained. Results of the deterministic sensitivity analysis were most sensitive to changes in discount rates for costs and care costs in the PD state. The PSA showed that the probability of atezolizumab being cost-effective at willingness-to-pay thresholds of $100,000 and $150,000 was 41% and 49%, respectively. Conclusions: First-line atezolizumab monotherapy had 0.6 life-years and 0.47 QALYs gained compared with pembrolizumab monotherapy and was estimated to be cost-effective (ICER $58,841/QALY). As the ICER falls below the US cost-effectiveness thresholds ( < $100,000-$150,000/QALY), clinicians and payers should consider atezolizumab monotherapy as a cost-effective 1L option for mNSCLC patients with high PD-L1 expression.