ABSTRACT: BACKGROUND:Major psychiatric disorders are growing public health concern that attributed 14% of the global burden of diseases. The management of major psychiatric disorders is challenging mainly due to medication non-adherence. However, there is a paucity of summarized evidence on the prevalence of psychotropic medication non-adherence and associated factors. Therefore, we aimed to summarize existing primary studies' finding to determine the pooled prevalence and factors associated with psychotropic medication non-adherence. METHODS:A total of 4504 studies written in English until December 31, 2017, were searched from the main databases (n =?3125) (PubMed (MEDLINE), Embase, CINAHL, PsycINFO, and Web of Science) and other relevant sources (mainly from Google Scholar, n =?1379). Study selection, screening, and data extraction were carried out independently by two authors. Observational studies that had been conducted among adult patients (18 years and older) with major psychiatric disorders were eligible for the selection process. Critical appraisal of the included studies was carried out using the Newcastle Ottawa Scale. Systematic synthesis of the studies was carried out to summarize factors associated with psychotropic medication non-adherence. Meta-analysis was carried using Stata 14. Random effects model was used to compute the pooled prevalence, and sub-group analysis at 95% confidence interval. RESULTS:Forty-six studies were included in the systematic review. Of these, 35 studies (schizophrenia (n?=?9), depressive (n?=?16), and bipolar (n?=?10) disorders) were included in the meta-analysis. Overall, 49% of major psychiatric disorder patients were non-adherent to their psychotropic medication. Of these, psychotropic medication non-adherence for schizophrenia, major depressive disorders, and bipolar disorders were 56%, 50%, and 44%, respectively. Individual patient's behaviors, lack of social support, clinical or treatment and illness-related, and health system factors influenced psychotropic medication non-adherence. CONCLUSION:Psychotropic medication non-adherence was high. It was influenced by various factors operating at different levels. Therefore, comprehensive intervention strategies should be designed to address factors associated with psychotropic medication non-adherence. SYSTEMATIC REVIEW REGISTRATION:PROSPERO CRD42017067436.