Purpose To assess diagnostic performance and reliability of Prostate-specific Membrane Antigen Reporting and Data System (PSMA-RADS) version 1.0 in evaluating prostate cancer (PCa) and compare it with the updated version (version 2.0). Materials and Methods This prospective, multicenter study was conducted between June 2022 and August 2024. Participants with PCa underwent gallium 68 (Ga) PSMA-11 PET/CT imaging and were divided into three groups: new diagnoses, biochemical recurrence (BCR), and follow-up. Three nuclear medicine radiologists independently interpreted the images using PSMA-RADS version 1.0, followed by a retrospective assessment using PSMA-RADS version 2.0. Diagnostic performance was calculated using linear mixed-model analysis. Histopathology and follow-up data served as reference standards. Interrater agreement was evaluated using the intraclass correlation coefficient (ICC). Results The study included 443 male participants (mean age, 68.6 years ± 8.1 [SD]) divided into new diagnoses ( = 164), BCR ( = 108), and follow-up ( = 171) groups. Compared with PSMA-RADS version 1.0, version 2.0 improved diagnostic accuracy in new diagnoses (95.9% vs 97.4%, = .02), BCR (92.6% vs 95.7%, = .004), and follow-up (88.7% vs 94.7%, < .001). Sensitivity substantially improved in follow-up cases (87.7% vs 95.7%, < .001). Interrater agreement was comparable between two versions, with lowest reliability in soft tissue evaluation (ICC = 0.36-0.50). Introduction of the PSMA-RADS 5T category to version 2.0 enhanced the characterization of treated metastases, improving correlation with prostate-specific antigen dynamics ( = 0.74 vs 0.61, < .001) and the discrimination of treatment response (88.7% vs 82.3%, = .02). Conclusion Both PSMA-RADS versions 1.0 and 2.0 were highly accurate and reliable for PCa imaging, with version 2.0 offering significant improvements, particularly in challenging follow-up and BCR cases. PET/CT, Urinary, Prostate, Neoplasms-Primary, Oncology, Comparative Studies, Prostate Cancer, PSMA-RADS, Diagnostic Performance, Reliability Clinical trial registration no.: NCT06359717 © RSNA, 2025.