Erectile dysfunction (ED) has serious negative consequences on both sexual experience and emotional well being and affects a broad range of age groups. The prevalence of ED is associated with increasing age and has been reported to be as high as 70%. Although the disorder is common and underdiagnosed, its treatment can significantly improve patients' quality of life. Systemic treatment with oral phosphodiesterase type-5 (PDE-5) inhibitors is the current standard of care for patients with ED. Some patients, however, have absolute contraindications for PDE-5 inhibitors. In addition, these agents can be associated with adverse effects. Furthermore, because PDE-5 inhibitors are not as effective in patients who have undergone radical prostatectomy or who have severe vascular disease, a substantial unmet medical need exists among patients who have ED as a result of these conditions. Consequently, PDE-5 inhibitor therapy is associated with a high rate of discontinuation, as are intracavernosal or transurethral therapies, which are inconvenient and invasive. Several studies, including four double-blind, placebo-controlled, Phase II trials, show that alprostadil topical cream is efficacious and well-tolerated in ED in patients with mild-to-severe symptoms, in those undergoing treatment for cardiovascular diseases and diabetes and in otherwise healthy ED patients. Thus, alprostadil topical cream is a potential first-choice alternative for ED in patients who do not respond or who cannot tolerate or do not accept PDE-5 inhibitor therapy.