Objective: Priapism is defined as prolonged and persistent erection of the penis without sexual stimulation. Etiologies of this condition are numerous. Treatment of priapism varies from a conservative medical to a drastic surgical approach. Recent findings indicate methylene blue (MB), a guanylate cyclase inhibitor, to be a potential inhibitor of endothelial–mediated cavernous relaxation. This prompted us to assess the feasibility, use and effectiveness of MB in the treatment of priapism. Methods: 12 patients were treated for priapism. Etiologies were: 10 drug–mediated (PGE1 or papaverine/phentolamine mixture) after corpus cavernosum injection therapy (CCIT); 1 leukemia–induced, and 1 idiopathic high–flow priapism. The age range for all patients was 13–67 years, the average duration of priapism was 5.5 h after CCIT. MB was administered after blood aspiration of the corpora cavernosa. 5 ml of MB was injected intracavernously (i.c.) and left for 5 min. MB was then aspirated and the penis compressed for an additional 5 min. Results: All patients with CCIT–induced priapism were cured with MB alone. The 2 patients who did not respond to MB underwent i.c. phenylephrine administration and embolization of the pudendal artery, respectively. The etiology and duration of priapism were the strongest predictors for success with i.c. administered MB. The primary side effects were a transient burning sensation and blue discoloration of the penis on injection of MB. The initial baseline erectile status was restored in all patients cured by MB. Conclusion: These results confirm that MB is a safe and highly effective treatment agent for short–term pharmacologically induced priapism. The application of MB shows virtually no significant side effects compared to the systemic and local complications induced by α–adrenergic agonists.