Non-adherence to antidepressant medications is a significant barrier to the successful treatment of depression in clinical practice. This review aims to systematically assess the effectiveness of interventions for improving antidepressant medication adherence among patients with unipolar depression, and to evaluate the effect of these interventions on depression clinical outcomes. MEDLINE, PsycINFO and EMBASE databases were searched for English-language randomised controlled trials published between January 1990 and December 2010 on interventions to improve antidepressant adherence. The impact of interventions on antidepressant medication adherence (compliance and persistence) and depression clinical outcomes was evaluated. Data concerning the quality of the included studies were also extracted. Twenty-six studies met the inclusion criteria. Interventions were classified as educational, behavioural and multifaceted interventions. A total of 28 interventions were tested, as two studies investigated two interventions each. Sixteen (57%) of the 28 interventions showed significant effects on antidepressant adherence outcomes, whereas 12 (43%) interventions demonstrated significant effects on both antidepressant adherence and depression outcomes. The interventions which showed significant improvement in outcomes were primarily multifaceted and complex, with proactive care management and involvement of mental health specialists. The most commonly used elements of multifaceted interventions included patient educational strategies, telephone follow-up to monitor patients' progress, as well as providing medication support and feedback to primary care providers. Overall, educational interventions alone were ineffective in improving antidepressant medication adherence. In conclusion, improving adherence to antidepressants requires a complex behavioural change and there is some evidence to support behavioural and multifaceted interventions as the most effective in improving antidepressant medication adherence and depression outcomes. More carefully designed and well-conducted studies are needed to clarify the effect of interventions in different patient populations and treatment settings.