Purpose <p>Oncological treatment in a substantial portion of patients with cancer of unknown primary (CUP) remains challenging due to limitations of conventional imaging and positron emission tomography/computed tomography with ¹⁸Fluor-fluorodeoxyglucose (¹⁸F-FDG-PET/CT). In head and neck-like CUP (HNCUP), several studies found significantly higher tracer-uptake and detection rates of primary tumors in ⁶⁸Gallium-labeled fibroblast activation protein inhibitor-PET/CT (⁶⁸Ga-FAPI-PET/CT). Here, we address a gap in CUP literature by retrospectively evaluating the diagnostic accuracy of both tracer in a head-to-head comparison of patients with single-site and oligometastatic extra-cervical CUP.</p> Methods <p>13 patients with extra-cervical CUP underwent both ¹⁸F-FDG- and ⁶⁸Ga-FAPI-PET/CT. Suspicious PET-positive lesions were delineated using the volume of interest-technique (50%-isocontour) followed by analysis of maximum and mean standardized uptake values (SUVmax/mean), target-to-background ratios (TBRmax/mean) and tumor-to-tissue ratios (TTRmax/mean). Descriptive analysis was performed and log-transformation was applied to meet model assumptions and stabilize variance. The difference between log-transformed ⁶⁸Ga-FAPI- and ¹⁸F-FDG-uptake values was used as outcome variables.</p> Results <p>21 metastases of 3 patients with single-site and 6 patients with oligometastasized CUP were analyzed. 4 patients with previously extirpated metastases showed no uptake. No increased detection rate of primary tumors could be observed by either tracer. Differences of TBRmax in all metastatic sites and of TTRmax in organ metastases were significant. ⁶⁸Ga-FAPI-PET/CT lead to detection of 5/21 additional metastases which were not clearly distinguishable in ¹⁸F-FDG-PET/CT.</p> Conclusion <p>Due to higher tissue contrast in organs, our findings suggest that ⁶⁸Ga-FAPI-PET/CT appears favourable compared to ¹⁸F-FDG-PET/CT particularly in patients with suspected distant metastases other than lymph nodes.</p>