Background: Definitive radiation therapy (dRT) is an effective initial treatment of intermediate-risk (IR) and high-risk (HR) prostate cancer (PCa). Positron emission tomography (PET) using small molecule probes targeting prostate-specific membrane antigen (PSMA PET) is superior to standard of care imaging (CT, MRI, bone scan) for detecting regional and distant metastatic PCa. PSMA PET thus has the potential to guide primary radiotherapy planning in patients and improve outcomes. The purpose of the present randomized trial is to evaluate the success rate of dRT for IR or HR PCa with and without planning based on PSMA PET. Methods: We will randomize 312 patients to proceed with standard dRT (control Arm 1, n=150), or undergo a PSMA PET scan prior to dRT planning (intervention arm 2, n = 162). In the control arm, dRT will be performed as routinely planned in accordance with initial stratification. In the intervention arm, the treating radiation oncologist can incorporate PSMA PET findings into the RT planning. We assume that approximately 8% of subjects randomized to arm 2 will be found to have M1 disease and thus will be more appropriate candidates for long-term systemic or multimodal therapy, rather than curative intent dRT. PET M1 patients will thus not be included in the analysis of the primary endpoint. The primary endpoint is the success rate of dRT measured as PFS after initiation of dRT. Progression is defined as (whichever occurs first): biochemical recurrence defined as a rise by 2 ng/mL or more above the nadir PSA (defined as the lowest PSA achieved) after radiotherapy with or without short-term hormonal therapy; appearance of metastasis or loco-regional recurrence (diagnosed by any imaging or biopsy); initiation of any new salvage therapy, or death from any cause. Discussion: This is the first randomized phase 3 prospective trial designed to determine whether PSMA PET molecular imaging can improve outcomes in patients with PCa who receive dRT. In this trial the incorporation of PSMA PET may improve the success rate of curative intent radiotherapy in two ways: to optimize patient selection and to personalizes the radiotherapy plan. Clinical trial registration: IND#147591, UCLA IRB #20-000378, ClinicalTrials.gov Identifier NCT04457245. Clinical trial information: NCT04457245