OBJECTIVES: The prognosis of non-small cell lung cancer (NSCLC) patients is determined by mediastinal lymph node involvement at the time of diagnosis. The objective of this study was to investigate the cost consequences of using endoscopic ultrasonography with fine-needle aspiration (EUS-FNA) instead of mediastinoscopy (MS) or explorative thoracotomy (ET) in patients with NSCLC and suspected mediastinal involvement on positron emission tomography (PET). METHODS: Potentially operable patients with NSCLC and positive PET were eligible. If EUS-FNA was negative or inconclusive, patients underwent MS. If MS was negative, ET was performed. If EUS-FNA was positive for malignancy, no ET was performed. The primary outcome was the reduction of invasive diagnostic procedures and as a result, the reduction of direct medical costs, assessed from the hospital viewpoint. The time horizon was the diagnostic trajectory until discharge from the hospital. RESULTS: Of 82 patients, 49 (60%) had positive EUS-FNA, and did not undergo invasive diagnostic procedures. In 33 patients (40%) EUS-FNA was either negative (6) or inconclusive (27). Surgical staging by MS or ET was performed in 26 of these 33 patients: 12 patients underwent MS, nine patients had ET, and four patients both procedures. The costs were $1590 for MS and $5822 for ET. The costs for EUS-FNA were $591. Assuming that, without EUS-FNA, all patients would undergo MS, and 15% would need additional ET to reach a diagnosis, the differences in total costs were calculated at $55,000. CONCLUSIONS: Introduction of EUS-FNA in the diagnostic work-up of NSCLC patients' leads to a reduction of invasive procedures, resulting in cost savings of $669 per patient.