The accuracy of mediastinal staging is of paramount importance in the management of patients with non-small cell lung cancer (NSCLC) to select only those patients who might benefit from upfront resection or multimodality treatment. Although CT is the imaging technique of first choice, its performance characteristics have led to an increased use of both EUS-FNA and (18)FDG-PET to improve (mediastinal) staging. In view of the relatively few studies employing both techniques simultaneously, we evaluated 20 consecutive patients (median age 70 years, range 48-83 years) with NSCLC in whom CT suggested N2 and/or N3 involvement. The sensitivity, specificity, PPV and NPV of EUS-FNA and (18)FDG-PET was 86%, 100%, 100%, 90%, and 100%, 89%, 88% and 100%, respectively. EUS-FNA confirmed the absence of malignancy in all patients with a negative (18)FDG-PET scan. Similarly, in the PET-positive patients, EUS-FNA confirmed malignancy in seven out of nine (78%) sites. Unnecessary surgery was prevented in six out of 16 patients otherwise considered as surgical candidates (37%). We conclude that both EUS-FNA and (18)FDG-PET have excellent operating characteristics. However, initial (18)FDG-PET findings should guide the complementary use of EUS-FNA to define treatment options and to prevent unnecessary surgery in selected patients.