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Abstract Background Researchers have not simultaneously compared the cost‐effectiveness of six immunotherapies with chemotherapy for advanced non‐small cell lung cancer. This study evaluated the cost‐effectiveness across different programmed death‐ligand 1 (PD‐L1) levels. Methods A Markov model with lifetime horizon was created for seven regimens: pembrolizumab plus chemotherapy (pembro‐chemo), nivolumab plus ipilimumab (nivo‐ipi), nivolumab, ipilimumab plus chemotherapy (nivo‐ipi‐chemo), atezolizumab plus chemotherapy (atezo‐chemo), atezolizumab, bevacizumab plus chemotherapy (atezo‐beva‐chemo), single‐agent pembrolizumab, and chemotherapy alone. Input parameters were derived from trial data, a network meta‐analysis, and other literature. We conducted the analysis from the perspective of US health care sector. Results For all patients without considering PD‐L1 expression, the incremental cost‐effectiveness ratio (ICER) of pembro‐chemo versus chemotherapy was $183,299 per quality‐adjusted life year (QALY). The preferred regimens based on ICERs differed by PD‐L1 levels. For patients with PD‐L1 ≥50%, pembrolizumab versus chemotherapy and pembro‐chemo versus pembrolizumab resulted in ICERs of $96,189 and $198,913 per QALY, respectively. The other strategies were dominated. For patients with PD‐L1 of 1%–49%, the ICER of pembro‐chemo comparing to chemotherapy was $218,159 per QALY. The other regimens were dominated by pembro‐chemo. For patients with PD‐L1 |