Anejaculation is a rare cause of infertility and adversely affects the general sense of well-being and perception of sexual life satisfaction. Evidence to support effective and noninvasive treatment for this ejaculatory disorder is lacking. This study aimed to evaluate the efficacy and safety of midodrine (a 1 -adrenergic receptor agonist) for the treatment of organic anejaculation but not spinal cord injury (SCI). A total of 128 patients were randomly assigned to oral midodrine 7.5-15 mg per day in a stepwise approach (group 1, n ¼ 64), or a similar regimen of placebo (group 2, n ¼ 64). They underwent a complete physical examination, echocardiography, 12-lead electrocardiogram, transrectal ultrasonography, complete blood count and blood chemistry. Hormonal assays included serum levels of luteinizing hormone, follicle-stimulating hormone, prolactin and testosterone. To rule out other sexual dysfunction, patients also completed the International Index of Erectile Function questionnaire. Psychiatric disorders were excluded by appropriate tests. Outcome measure was reversal of the anejaculation. None of the patients in the placebo group achieved antegrade or retrograde ejaculation. At the end of study, antegrade, retrograde and antegrade þ retrograde ejaculation occurred in 18 (29.5%), 8 (13.1%) and 9 (14.8%) patients in midodrine group, respectively (all P ¼ 0.01). The most and least favorable responses were among patients with multiple sclerosis and bilateral sympathectomy, respectively. Midodrine improved ejaculation function in a dose-dependent manner. Four participants (6.3%) in midodrine group discontinued this study for reasons of adverse events. In patients with organic anejaculation but without SCI midodrine can reverse anejaculation in more than 50% of patients. Further studies are needed, however, for the evaluation of different treatment regimens in anejaculation therapy.