Background and Aims: Relaxation of cavernous smooth muscle is a parasympathetic and non-adrenergic, non-cholinergic mediated process which requires nitric oxide (NO). NO is synthesized from L-arginine by NO synthase (NOS). Some studies report good clinical results under oral L-arginine medication in the treatment of erectile dysfunction. We examined the effectiveness and safety of L-arginine in the treatment of mixed-type impotence. Methods: 32 patients (mean age 51.6 years) with mixed-type impotence diagnosed according to the results of sexual history and urological examination were enrolled in a randomized, placebo-controlled, crossover comparison of an oral placebo with 3 × 500 mg L-arginine/day. A validated questionnaire (KEED) was used to define the grade of impotence with a score. The treatment consisted of two 17-day courses (50 tablets). After a 7-day washout period the patients who initially received the placebo for 17 days were switched to L-arginine and vice versa. We assessed the efficacy with the validated questionnaire at the end of each drug period. Results: 30 patients (94%) completed the whole treatment schedule. Five (17%) patients reported a significant improvement in erectile function at the end of the L-arginine phase and 6 (20%) patients after the placebo period. 17 (56%) patients showed little improvement with L-arginine and 13 (43%) with placebo. In 8 patients (27%) of the verum group there was either no change in the ED score or even a slight worsening. No statistical difference in the impotence scores were found. No drug-related adverse effects occurred with L-arginine treatment. Conclusion: Oral L-arginine 3 × 500 mg/day is not better than placebo as a first-line treatment for mixed-type impotence.