The monamine oxidase (MAO) inhibitor selegiline is selective for MAO-B at the low oral dosages used in the treatment of Parkinson's disease. However, MAO-A is also inhibited at the high oral dosages needed to effectively treat depression (not an approved indication), necessitating a tyramine-restricted diet. The selegiline transdermal system was designed to deliver antidepressant drug concentrations to the CNS, without substantially impairing small intestine MAO-A activity. At the target dose of 6 mg/24 hours, tyramine dietary restrictions are not needed. Short-term treatment with fixed (6 mg/24 hours) or flexible (6, 9 or 12 mg/24 hours) doses of selegiline transdermal system was superior to placebo on most measures of antidepressant activity in 6- or 8-week, randomised, double-blind, multicentre studies in adult outpatients with major depressive disorder (MDD). Likewise, long-term treatment with a fixed dose of selegiline transdermal system 6 mg/24 hours was superior to placebo as maintenance therapy in a 52-week, randomised, double-blind, multicentre, relapse-prevention trial in patients with MDD. Selegiline transdermal system therapy was generally well tolerated in placebo-controlled studies; application site reactions, mostly of mild to moderate severity, were the most commonly reported adverse events. The incidence of sexual adverse effects and weight gain was low and similar to that with placebo.