Background: Despite the use of integrated positron emission tomography and computed tomography scans in patients with nonsmall-cell lung cancer, N2 disease is often missed. Knowledge of the N2 station most likely to be malignant based on the lobar location of the primary may help guide biopsies. Methods: A retrospective review of an electronic prospective database of patients with nonsmall-cell lung cancer who underwent positron emission tomography and computed tomography clinical staging and had nodal biopsy or resection with complete lymphadenectomy, or both. Results: The incidence and location of N2 disease of the 954 patients based on the location of the primary tumor was as follows: for right upper lobe cancers, 27% had N2 disease, most commonly in the 4R (23%); right middle lobe, 15%, most commonly in the 4R (8%) and the 7th station (6%); right lower lobe, 30%, most commonly in the 4R (15%) and the 7th station (14%); left upper lobe, 20%, most commonly in the 6 (16%); and left lower lobe, 22%, most commonly in the 7 (8%). Patients with right middle lobe cancer were more likely to have N1 disease (p = 0.014). Skip metastases (no N1, but N2 disease) was most common with left upper lobe lesions. Patients with right-sided cancers were more likely to have N2 disease compared with patients who had left-sided lesions (27% versus 21%, p = 0.02). Conclusions: There is a distinct predilection for the location of N2 disease based on the lobar location of primary nonsmall-cell lung cancer. We recommend the consideration of video-assisted thoracoscopy for biopsy of the 5 and 6 stations for patients with left upper lobe lesions, mediastinoscopy for right upper lobe lesions, and esophageal ultrasound with fine-needle aspiration for right lower lobe, left lower lobe, and right middle lobe lesions. Right-sided lesions are more likely to have N2 disease. © 2006 The Society of Thoracic Surgeons.