PURPOSE: To investigate efficacy and safety of platelet-rich plasma (PRP) intra-plaque injections in Peyronie's disease (PD) patients. METHODS: Three injections of 6 mL PRP were performed two weeks apart. Patients were evaluated at baseline (T0, first injection), after two weeks (T1, second injection), and four weeks after the third injection (T2). The curvature angle of the erect penis, plaque size, dedicated sexual function questionnaires (PD questionnaire-PDQ, and International Index of Erectile Function five-items - IIEF-5) scores, and adverse events/side effects were evaluated. RESULTS: Overall, 72 patients were included. Median age was 60 years, and median BMI was 23.1 kg/m. Plaques were more frequently located at the middle third of the penis (n = 43); penile curvature direction was more frequently dorsal (n = 45). During follow up median plaque size decreased from 11.1 mm at T0 to 8.2 mm at T2 (p = 0.004), and median penile curvature decreased from 50.0° at T0 to 40.0° at T2 (p < 0.001). At the same timepoints, a statistically significant reduction was observed for all the three domains of the PDQ (PDQ1:p = 0.006, PDQ2:p = 0.002, PDQ3:p < 0.001), but not for the IIEF-5 (p = 0.3). At univariable linear regression analysis, testing the association between BMI and median penile curvature difference from the first and last evaluation, a tendency towards statistical significance was observed (β = -1.28, p = 0.055). No adverse events/side effect were registered. CONCLUSION: PRP is a safe and effective treatment option in men with PD, rapidly reducing plaques size and penile curvature angle, thus positively influencing sexual function. The higher the BMI the lower benefit might be derived from PRP injection.