INTRODUCTION: Stimulant medications are the most effective drugs in the treatment of attention-deficit hyperactivity disorder (ADHD) in children and in adults. However, some patients do not respond to this treatment and other patients suffer from adverse effects. Very often there are also comorbid disorders that warrant treatment or there is somatic comorbidity that precludes the prescription of stimulants. As a result, alternative treatments for the treatment of ADHD have been explored, such as antidepressant agents. In this systematic review the evidence base for the effect of antidepressants for ADHD in adult patients is determined. METHODS: Electronic and hand searches were conducted in order to identify clinical trials studying antidepressants for the treatment of ADHD in adult patients. The trials were screened for methodological characteristics and treatment-effect sizes. The odds ratio was calculated for randomized controlled trials with bupropion. A descriptive review of all the randomized controlled studies and an overview of the nonrandomized studies was developed. RESULTS: Only eight randomized controlled trials were retrieved with four different compounds. Five studies concerned bupropion and the meta-analysis indicates a beneficial effect for bupropion compared with placebo as measured with the Clinical Global Improvement Scale (odds ratio 2.42 [95% CI 1.09 to 5.36]). Several studies suffer from clinical and methodological shortcomings, such as exclusion of patients with comorbid disorders, short treatment duration, or a lack of information with respect to the randomization procedure. CONCLUSION: Although there is a need for alternative interventions for the treatment of ADHD, such as with antidepressant agents, the evidence base is not large. Only treatment with bupropion seems to have a medium-range effect size, but this is less than that of stimulant medications.