Associate Editor Michael G. Wyllie Editorial Board Ian Eardley, UK Jean Fourcroy, USA Sidney Glina, Brazil Julia Heiman, USA Chris McMahon, Australia Bob Millar, UK Alvaro Morales, Canada Michael Perelman, USA Marcel Waldinger, Netherlands OBJECTIVES: To determine whether a long‐term single daily oral dose of a longer half‐life phosphodiesterase‐5 (PDE5) inhibitor, tadalafil, has a similar effect to that of the shorter half‐life PDE5 inhibitors sildenafil and vardenafil, and can prevent the fibrosis and resultant corporal veno‐occlusive dysfunction (CVOD) occurring after cavernosal nerve (CN) injury. MATERIALS AND METHODS: Male rats (10 per group) had either a sham operation, unilateral CN resection (CNR) or bilateral CNR, and were left untreated or given retrolingually 5 mg/kg per day of tadalafil. After 45 days, CVOD was assessed via cavernosometry, and the underlying corporal tissue changes were examined by immunohistochemistry and histochemistry (followed by quantitative image analysis), Western blots, and ad hoc methods. RESULTS: Tadalafil treatment normalized the low response to papaverine and high drop rate in the intracavernosal pressure measured by cavernosometry after CNR compared with sham‐operated rats. Tadalafil also normalized the increase in penile shaft collagen content, and the reduction in corporal smooth muscle cell (SMC) content, SMC/collagen, and replication index, and improved the lower collagen III/I ratio and the increase in apoptotic index, caused by CNR, compared with sham operation. There were no effects of tadalafil on increased transforming growth factor β1, inducible nitric oxide synthase and xanthine oxidoreductase levels. CONCLUSIONS: A long‐term single daily dose of tadalafil prevented CVOD and the underlying corporal fibrosis in the rat caused by CN damage, as effectively as the previously reported continuous treatment with vardenafil or sildenafil, through a cGMP‐related mechanism that appears to be independent of inducible nitric oxide synthase induction.