Background: In the CASPIAN trial, durvalumab + chemotherapy demonstrated significant improvements in overall survival compared with chemotherapy alone in patients with extensive-stage small cell lung cancer (SCLC). We aimed to assess the cost-effectiveness of durvalumab in patients with extensive-stage SCLC from the US healthcare system perspective. Patients and Methods: A comprehensive Markov model was adapted to evaluate cost and effectiveness of durvalumab combination versus platinum/etoposide alone in the first-line therapy of extensive-stage SCLC based on data from the CASPIAN study. The main endpoints included total costs, life years (LYs), quality-adjusted life-years (QALYs), and incremental cost-e-ectiveness ratios (ICERs). Model robustness was assessed with sensitivity analysis, and additional subgroup analyses were also performed. Results: Durvalumab + chemotherapy therapy resulted in an additional 0.27 LYs and 0.20 QALYs, resulting in an ICER of $464,711.90 per QALY versus the chemotherapy treatment. The cost of durvalumab has the greatest inﬂuence on this model. Subgroup analyses showed that the ICER remained higher than $150,000/QALY (the willingness-to-pay threshold in the United States) across all patient subgroups. Conclusions: Durvalumab in combination with platinum/etoposide is not a cost-effective option in the first-line treatment of patients with extensive-stage SCLC.