Exact staging of locoregional lymph node (LN) disease in non-small cell lung cancer (NSCLC) is of considerable clinical interest. Computed tomography (CT) is not very accurate for this purpose. In the past years, we performed several prospective studies examining the role of [18F]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) in this setting. We compared the accuracy of CT, PET, and PET read with the anatomical aid of CT images in the distinction of early-stage operable cases (i.e., without metastatic LN or with only hilar metastatic LN) versus locally advanced cases (with metastatic mediastinal LN). LNs on PET were recorded as metastatic if the FDG-uptake was more intense than the mediastinal blood pool activity. In 105 patients (or an analysis of 980 LN stations), the accuracy of PET (85%) was significantly better than that of CT (64%; P = 0.0003). Visual correlation with CT images further improved the results to an accuracy of 90%. We also examined the value of different acquisition protocols and interpretation algorithms. The use of Standardized Uptake Values (SUVs) of LNs, or of anatometabolic PET-CT-fusion images, did not prove to be of additional value compared to visual PET-reading and correlation with the CT images. On the condition that positive-LN findings on PET are always confirmed by mediastinoscopy, a simple whole-body acquisition protocol is adequate. We conclude that FDG-PET plays an important role in LN-staging in NSCLC. The very high negative predictive value of mediastinal FDG-PET is able to reduce the need for invasive surgical staging substantially.