Intracavernosal injection of Trimix (a combination of phentolamine, papaverine, and alprostadil) is used for the treatment of erectile dysfunction. A rare but serious side effect of Trimix is priapism, a persistent erection lasting for more than four hours. Penoscrotal decompression is a newer technique being used to treat refractory and persistent ischemic priapism. Here, we report a unique case of priapism treated with penoscrotal decompression in a patient following an unmeasured injection of Trimix.A 36-year-old male presented to the emergency room complaining of a persistent painful erection over the previous five days following a Trimix injection and illicit methamphetamine use. At bedside, aspiration and irrigation were attempted without any improvement. Phenylephrine injection was contraindicated due to sinus tachycardia. The patient then underwent bilateral penoscrotal decompression on day six post-Trimix injection. The procedure was successful with a resolution of the erection, though some moderate corporal fibrosis was noted. At a 10-day follow-up, the patient reported moderate pain in his penis but had regained complete potency.Misuse of Trimix can cause persistent ischemic priapism. Penoscrotal decompression is a novel technique used to treat persistent ischemic priapism and has been shown to have positive efficacy in the resolution of priapism as well as in salvaging erectile function. To our knowledge, treatment of persistent priapism with penoscrotal decompression after using Trimix has not yet been reported in the literature. Given the rarity of this, our report highlights a unique case that has potential benefit for future practitioners who are faced with this clinical scenario.