Background & Aims: Accurate assessment of mediastinal lymph nodes is vital for optimum treatment allocation in lung cancer patients. Currently available strategies fail to identify many patients with advanced mediastinal disease, resulting in unnecessary surgery. We prospectively compared 2 promising new modalities, positron emission tomography (PET) and endoscopic ultrasound (EUS), for staging mediastinal lymph nodes. Methods: Consenting patients with lung cancer who also were suitable candidates for surgery were enrolled in the study. Patients underwent both PET and EUS. Outcomes were analyzed by surgery results or follow-up with serial imaging. Results: Seventy-two eligible patients were enrolled, and adequate data were available for 65 patients. The final diagnosis was based on tissue analysis in 59 patients and 1-year radiologic follow-up evaluation in 6 patients. PET correctly diagnosed mediastinal lymph node status in 77% of patients, and EUS fine-needle aspiration was correct in 94% of patients (P = .012). The overall sensitivity, specificity, and accuracy of PET were 61%, 91%, and 77% compared with 87%, 100%, and 94% for EUS. We estimated that EUS obviated a surgical procedure in 55% (95% confidence interval, 40%-69%) of patients with radiologic evidence of mediastinal metastasis, and in 22% (95% confidence interval, 10%-41%) of patients without radiologic evidence of mediastinal metastasis. Conclusions: EUS fine-needle aspiration was more accurate than PET in staging mediastinal lymph nodes in lung cancer patients, and resulted in a substantial reduction in mediastinoscopy and thoracotomy.