The concept of melancholia has been associated with psychiatric nosology for centuries. Nevertheless, its definition, relationship to the contemporary concept of Major Depressive Disorder, and clinical implications remain uncertain. In a total sample of 3211 closely evaluated patient-subjects diagnosed with DSM-5 Major Depressive or Bipolar Disorder and meeting DSM-5 criteria for major depression with melancholic features or not at a European mood disorder center, we matched 1833 for depression severity (baseline HDRS21 score ≥18) and compared rates and ratings of characteristics of interest between the subgroups, using bivariate and multivariate methods. Observed prevalence of melancholic features was 35.2% in the 1833 subjects matched for severity, and 21.0% among all 3211 subjects. Diagnosis was highly dependent on depression-severity measured three ways. Very few clinical characteristics differed between melancholic and nonmelancholic subjects matched for illness-severity; more suicidal ideation with melancholic features was a notable exception. Study findings leave the distinction of melancholic features from depression-severity unclear and the potential clinical value of diagnosing melancholic features uncertain.