OBJECTIVE: Medication non-adherence in mental health problems has social and economic costs. The objective of the study was to review the cost-effectiveness of interventions to enhance medication adherence in patients with mental health problems. METHODS: The update of a previous systematic review was performed. Databases were searched in June 2019: MEDLINE, PSYCINFO, EMBASE, CINAHL, CRD, WOS. Cost-effectiveness studies comparing an intervention to improve the medication adherence with other interventions/usual care in adults with mental health problems were included. Data were extracted, methodological quality of the studies was assessed and a narrative synthesis was performed. RESULTS: Nine studies were included in the review. The interventions that showed medication adherence increase were: a financial incentive when depot injection was taken by patients with psychotic disorders, a value-based benefit design policy including copayment and counselling in a company setting, and a medication treatment decision supported by a pharmacogenetic test. The other studies (coaching by pharmacists; a psychological and educational intervention at health care centres) did not find differences between groups. No study found cost differences between alternatives. CONCLUSIONS: Interventions to improve medication adherence in adults with mental health problems could be cost-effective, especially those based on financial incentives, although more research is needed. KEYPOINTS There are several types of interventions designed to enhance medication adherence in patients with mental health problems. Few of them have demonstrated cost-effectiveness. Two studies found that a financial incentive per depot injection in patients with psychotic disorders improved the medication adherence. Two other studies found improvement in adherence due to two specific interventions: a value-based benefit design policy in a company setting and a pharmacogenetic test supporting the medication treatment decision. No study found differences in costs between the intervention and the comparator. More research is needed to implement cost-effective interventions.