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Introduction Our aim was to characterize the diagnostic accuracy indices for nodal (N)-staging with [ 18 F]FDG Total-Body (TB) and short-axial field-of-view (SAFOV) PET/CT in non-small cell lung cancer (NSCLC) patients referred for staging or restaging. Methods In this prospective single center cross-over head-to-head comparative study 48 patients underwent [ 18 F]FDG TB and SAFOV PET/CT on the same day. In total 700 lymph node levels (1R/L, 2R/L, 3a/p, 4R/L, 5, 6, 7, 8R/L, 9R/L, 10-14R/L) of 28 patients could be correlated to a composite reference standard (histopathological correlation, imaging after localized or systemic treatment), which allowed determination of true positive (TP), false positive (FP), true negative (TN) and false negative (FN) lesions. Lymph nodes were characterized semi-quantitatively by maximum standardized uptake value (SUV max ), tumor-to-background ratio (TBR), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) leading to threshold for each scanner. Results TB and SAFOV PET/CT showed high diagnostic accuracy indices for patient-based N-staging. Sensitivity and specificity were 86.0% (CI: 77.0–95.0%) and 98.3% (CI: 97.3–99.3%) for TB; 77.2% (CI: 66.3–88.1%) and 97.4% (CI: 96.1–98.6%) for SAFOV PET. Positive predictive value was higher for TB (81.7%, CI: 71.9–91.5%) compared to SAFOV PET (72.1%, CI: 60.9–83.4%). However, this finding was not statistically significant ( p  = 0.08). Negative predictive values for TB (98.6%, CI: 97.9–99.6%) and SAFOV PET/CT (98.0%, CI: 96.9–99.1%) were comparable. Overall, NSCLC N-staging was affected in six cases on SAFOV and only in one case on TB PET/CT. Semi-quantitative analysis revealed a threshold of SUV max 3.0 to detect TP lesions on both scanners. However, TBR, MTV and TLG thresholds were lower on TB compared to SAFOV PET (TBR: 1.2 vs. 1.7, MTV: 0.5 ml vs. 1.0 ml and TLG: 1.0 ml vs. 3.0 ml). Conclusion TB and SAFOV PET/CT showed high diagnostic accuracy indices for N-staging in NSCLC patients. Sensitivity and PPV on TB PET/CT were slightly higher, compared to SAFOV PET/CT without statistical significance. However, TB PET/CT showed lower rate of incorrect N-staging and lower semi-quantitative thresholds for the detection positive mediastinal lymph nodes. Therefore, TB PET/CT might be advantageous in detecting small and low [ 18 F]FDG-avidity mediastinal lymph node metastases in NSCLC patients.