Background: PSMA (Prostate Specific Membrane Antigen) and GRP-R (Gastrin Releasing Peptide Receptor) are overexpressed on prostatic cancer cells and can be targeted with a PSMA inhibitor such as ⁶⁸Ga-PSMA-617 (Liu 2018) or a GRP-R antagonist such as ⁶⁸Ga-RM2 (Touijer 2019). We aimed to compare ⁶⁸Ga-PSMA-617 PET/CT and ⁶⁸Ga-RM2 PET/CT at initial staging of prostate cancer. Methods: We prospectively enrolled 10 treatment-naïve patients with biopsy-confirmed prostate cancer. Fifteen lesions were found (two with Gleason score (GS) 6; seven GS 7(3+4), two GS 7(4+3) and four GS ≥ 8). ⁶⁸Ga-PSMA-617 PET/CT and ⁶⁸Ga-RM2 PET/CT were randomly performed before prostatectomy with imaging at 1 and 2 hours after injection (2MBq/kg). Manual (MS) and automatic (AS) segmentation were performed on each PET imaging and then compared to histology (standard-of- truth). Prostatectomy samples were analyzed by an experimented pathologist who identified and staged each lesion according to GS. Each prostatectomy slice available was scanned for comparison between PET and histologic segmentation. Uptake intensity (SUVmax) and signal-to-noise ratio (SNR) relative to non-lesional prostate gland parenchyma were analyzed. Per-lesion analysis was performed on final GS (prostatectomy). Results: Using AS, ⁶⁸Ga-RM2 PET/CT showed better sensitivity (Se) than ⁶⁸Ga-PSMA-617 PET/CT: (0.85 vs 0.75) and better specificity (Sp) (0.89 vs 0.60). MS found similar Se (0.94 vs 0.93) but better Sp (0.89 vs 0.80) with ⁶⁸Ga-RM2 PET/CT. SNR of ⁶⁸Ga-RM2 PET/CT was high whatever the GS was; while ⁶⁸Ga-PSMA-617 PET/CT exhibited higher SNR in high GS (p = 0.044). Finally, in low GS, SNR of ⁶⁸Ga-RM2 PET/CT was significantly higher than ⁶⁸Ga-PSMA-617 PET/CT (p = 0.004). Conclusions: GRP-R-targeting and PSMA-targeting have been previously compared in patients with biochemically recurrence (Minamimoto 2016) but not at primary staging. Our initial results, in this indication, showed great diagnostic performance of ⁶⁸Ga-RM2 PET/CT compared to ⁶⁸Ga-PSMA-617 PET/CT to characterize low Gleason score tumors. ⁶⁸Ga-PSMA-617 PET/CT is promising for initial staging of high Gleason score tumors. These results need to be confirmed in a larger study.