Purpose <p>To compare prostate-specific membrane antigen (PSMA) and fibroblast activation-protein inhibitor (FAPI) targeted PET/CT imaging to assess possible theranostic combination strategies of both tracers in metastatic prostate cancer (mPC).</p> Methods <p>This prospective study enrolled patients with mPC who underwent long-axial field-of-view whole-body PET/CT with ¹⁸F-DCFPyL and ¹⁸F-FAPI-74 within two weeks. Fifteen patients had hormone sensitive (mHSPC) and 24 castration-resistant (mCRPC) disease. Scans were reviewed according to predefined criteria, with up to five metastases per anatomical region evaluated. Lesions were categorized in four groups as skeletal, pelvic nodal, extrapelvic nodal, or visceral. SUVmax and volumetric parameters were measured for each lesion and at the patient level.</p> Results <p>A total of 1365 lesions were identified in 39 patients. ¹⁸F-DCFPyL PET/CT detected 1351 lesions (99%). In contrast, ¹⁸F–FAPI-74 identified only 788 (58%) lesions in the PSMA-guided analysis and 523 (38%) lesions in the independent analysis. Median lesion SUVmax was higher for PSMA (24) than for FAPI (5.4) (p &lt; 0.001). Visceral metastases constituted 3% of lesions with both tracers and tended to be more often FAPI-avid (64%) compared to other lesion groups. Only 14 (1%) of lesions were FAPI-positive and PSMA-negative. In whole-tumor burden analysis, median tracer-positive tumor volume on ¹⁸F-DCFPyL PET/CT was 85&#xa0;mL and on ¹⁸F-FAPI-74 PET/CT only 10&#xa0;mL (p &lt; 0.001).</p> Conclusion <p>In mPC, PSMA PET/CT remains the preferred molecular imaging method. Our findings suggest only a limited role of FAPI radioligand therapy. FAPI theranostics should focus on patients with visceral metastases and specific histological subtypes beyond acinar adenocarcinoma.</p> Clinical Trial Registration: EudraCT <p>2022–003788-13. Registered 21 September 2023</p>