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To assess the cost-effectiveness of various modes of mediastinal staging in non–small cell lung cancer (NSCLC) in a single-payer health care system.We performed a decision analysis to compare the health outcomes and costs of 4 mediastinal staging strategies: no invasive staging, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), mediastinoscopy, and EBUS-TBNA followed by mediastinoscopy if EBUS-TBNA is negative. We determined incremental cost effectiveness ratios (ICER) for all strategies and performed comprehensive deterministic sensitivity analyses using a willingness to pay threshold of $80,000/quality adjusted life year (QALY).Under the base-case scenario, the no invasive mediastinal staging strategy was least effective (QALY, 5.80) and least expensive ($11,863), followed by mediastinoscopy, EBUS-TBNA, and EBUS-TBNA followed by mediastinoscopy with 5.86, 5.87, and 5.88 QALYs, respectively. The ICER was ˜$26,000/QALY for EBUS-TBNA staging and ˜$1,400,000/QALY for EBUS-TBNA followed by mediastinoscopy. The mediastinoscopy strategy was dominated. Once pN2 exceeds 2.5%, EBUS-TBNA staging is cost-effective (˜$80,000/QALY). Once the pN2 reaches 57%, EBUS-TBNA followed by mediastinoscopy is cost-effective (ICER ˜$79,000/QALY). Once EBUS-TBNA sensitivity exceeds 25%, EBUS-TBNA staging is cost-effective (ICER ˜$79,000/QALY). Once pN2 exceeds 25%, confirmatory mediastinoscopy should be added, in cases of EBUS-TBNA sensitivity ≤ 60%.Invasive mediastinal staging in NSCLC is unlikely to be cost-effective in clinical N0 patients if pN2 <2.5%. In patients with probability of mediastinal metastasis between 2.5% and 57% EBUS-TBNA is cost-effective as the only staging modality. Confirmatory mediastinoscopy should be considered in high-risk patients (pN2 > 57%) in case of negative EBUS-TBNA.