Molecular imaging of muscle-invasive bladder cancer (MBC) is restricted to its locoregional and distant metastases, since most radiopharmaceuticals have a urinary excretion that limits the visualization of the primary tumor. ⁶⁴ CuCl ₂ _, a positron-emitting radiotracer with nearly exclusive biliary elimination, could be well suited to exploring urinary tract neoplasms. In this study, we evaluated the feasibility of ⁶⁴ CuCl ₂ -based staging of patients with MBC; furthermore, we compared the diagnostic capability of this method with those of the current gold standards, that is, contrast-enhanced CT (ceCT) and ¹⁸ F-FDG PET/CT. Methods: We prospectively enrolled patients referred to our institution for pathology-confirmed MBC staging/restaging between September 2021 and January 2023. All patients underwent ceCT, ¹⁸ F-FDG, and ⁶⁴ CuCl ₂ PET/CT within 2 wk. Patient-based analysis and lesion-based analysis were performed for all of the potentially affected districts (overall, bladder wall, lymph nodes, skeleton, liver, lung, and pelvic soft tissue). Results: Forty-two patients (9 women) were enrolled. Thirty-six (86%) had evidence of disease, with a total of 353 disease sites. On patient-based analysis, ceCT and ⁶⁴ CuCl ₂ PET/CT showed higher sensitivity than ¹⁸ F-FDG PET/CT in detecting the primary tumor (P < 0.001); moreover, ⁶⁴ CuCl ₂ PET/CT was slightly more sensitive than ¹⁸ F-FDG PET/CT in disclosing soft-tissue lesions (P < 0.05). Both PET methods were more specific and accurate than ceCT in classifying nodal lesions (P < 0.05). On lesion-based analysis, ⁶⁴ CuCl ₂ PET/CT outperformed ¹⁸ F-FDG PET/CT and ceCT in detecting disease localizations overall (P < 0.001), in the lymph nodes (P < 0.01), in the skeleton (P < 0.001), and in the soft tissue (P < 0.05). Conclusion: ⁶⁴ CuCl ₂ PET/CT appears to be a sensitive modality for staging/restaging of MBC and might represent a "one-stop shop" diagnostic method in these scenarios.