The purpose of this work was to evaluate the additional value of whole-body positron emission tomography (WB-PET) in the distant staging of non-small-cell lung cancer (NSCLC). One hundred forty-four patients with NSCLC in whom conventional staging (CS) was negative or equivocal for metastases, and who underwent WB-PET as part of their initial work-up, were retrospectively analyzed. Conventional staging consisted of thoracic computed tomography (CT), upper abdominal ultrasound and/or CT, and bone scintigraphy or brain CT on indication. Final M stage was based on histology, additional imaging, or follow-up of = 18 months. An additional lesion suspect for metastasis was found on WB-PET in 11 patients. This was true positive in 7 (3 bone, 1 retroperitoneal lymph nodes, 1 lung, and 2 asymptomatic coexisting colorectal cancer) and false positive in 4 patients (3 bowel, 1 breast). Twenty-four lesions in 21 patients remained equivocal after CS. Whole- body PET correctly characterized 20 lesions in 18 patients as true positive (n = 1) or true negative (n = 19). Whole-body PET was false positive in one patient (adrenal adenoma) and false negative in 2 patients (2 bone, 1 lung lesion). Despite negative results of modern CS and WB-PET, 16 of 86 patients (19%) who underwent a curative resection, experienced a systemic relapse. After thorough modern CS, WB-PET correctly detected additional distant malignant lesions in only 5% of the patients, while the combined staging strategy probably still misses micrometastatic disease in one fifth of the patients. The most important contribution of WB-PET was its ability to exclude malignancy in the majority of distant lesions with equivocal CS.