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Background: Phosphodiesterase type 5 (PDE5) inhibitor labeling states that these agents should not be used in conjunction with other erectogenic medications for fear of priapism occurring. Aim: We explored the risk of priapism and prolonged erections in men in our post–radical prostatectomy (RP) penile injection program who were using regular PDE5 inhibitor and intracavernosal injections (ICIs) as part of their rehabilitation program. Methods: The study cohort included men on penile injection therapy who (1) were taking tadalafil 5 mg daily or taking sildenafil 25 mg on noninjection days, (2) had an RP, (3) were using their respective PDE5 inhibitor regularly at the time of penile injection training, and (4) complied with the program instructions regarding penile injection use. Demographics, comorbidity details, PDE5 inhibitor dose and utilization, and injection dose and utilization data were collected. All patients underwent in-office injection training and used trimix (papaverine/phentolamine/prostaglandin E1) as the intracavernosal medication. Outcomes: Priapism was defined as a patient self-reported penetration hardness erection ≥4 hours in duration, while prolonged erection was defined as a penetration hardness erection lasting ≥2 hours. Results: A total of 112 tadalafil users and 364 sildenafil users were compared. Mean age and duration post-RP were 62 ± 14 years and 5.2 ± 12 months, respectively, and there was no difference between tadalafil and sildenafil groups. The mean trimix dose was tadalafil 24 ± 24 units and sildenafil 31 ± 37 units (P < .05). Priapism occurred in 2 (1.7%) of 112 tadalafil users and 5 (1.4%) of 364 sildenafil users (P = .47). Excluding those men experiencing priapism on any occasion, those with any reported penetration hardness erection lasting ≥2 hours were 7 (6.3%) of 112 tadalafil users and 12 (3.3%) of 364 sildenafil users (P < .01). A total of 53% of these prolonged erections occurred within the first 6 injections at home (no difference between tadalafil and sildenafil groups). Clinical Implications: We emphasize the need for continued monitoring and education on proper injection techniques to minimize the risk of adverse events in ICI and PDE5 inhibitor combination therapy. Strengths & Limitations: This study has a relatively large patient population with a considerable follow-up time. Additionally, the rigorous training, education, and monitoring of the participants, as well as the use of formal definitions for priapism and prolonged erections, enhances the accuracy and reliability of the results. However, there are some limitations, such as social desirability, confounding factors, and recall bias. Conclusion: There is no significant difference in the incidence of priapism in an ICI program in which men combine ICI with tadalafil or sildenafil. However, tadalafil patients had a higher rate of prolonged erections, which was found to occur mostly early during the titration phase. [ABSTRACT FROM AUTHOR]