OBJECTIVES: Early identification of patients with major depressive disorder (MDD) who cannot be managed by general psychiatric services and require highly specialized mental healthcare could enhance need-based patient stratification. This, in turn, may reduce the number of treatment steps needed to achieve and sustain an adequate treatment response. The development of a valid tool to identify patients with MDD in need of highly specialized care is hampered by the lack of a comprehensive understanding of early indicators that distinguish patients with and without a need for highly specialized MDD care. The aim of this study, therefore, was to systematically review studies on early indicators of patients with MDD likely in need of highly specialized care. METHODS:  A structured literature search was performed of the PubMed and the PsycINFO databases following PRISMA guidelines. Two reviewers independently assessed study eligibility and determined the quality of the identified studies. Three reviewers independently executed data extraction by using a pre-piloted, standardized extraction form. The resulting early indicators were grouped by topical similarity, creating a concise summary of the findings. RESULTS:  The systematic search of all databases yielded a total of 7,360 references, of which sixteen were eligible for inclusion. The sixteen papers yielded a total of 48 unique early indicators. Overall, a more pronounced depression severity, a younger onset age, a history of prior poor treatment response, psychiatric comorbidity, somatic comorbidity, childhood trauma, psychosocial impairment, older age, and a socioeconomically disadvantaged status were found to be associated with proxies of need for highly specialized MDD care. CONCLUSIONS:  Several early indicators are associated with the need for highly specialized MDD care. These indicators provide easily measurable factors that may serve as a starting point for the development of a valid tool to identify patients with MDD in need of highly specialized care.