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We investigated the predictive effect of psychological defenses on the course of major depression in a subsample of psychiatric patients from a larger study. We tested the hypothesis that a group of eight defenses, associated with depression in previous research, would predict outcome of major depression. After an intake interview, 37 patients were rated on all DSM-III-R Axes, the SCL-90-R, and 28 defenses, using the Defense Mechanism Rating Scales. At 6-month follow-up interview, SCL-90-R and Global Assessment and Functioning (GAF) were redetermined on 34 (92%), 16 of whom had major depression at intake. Overall Defensive Functioning (ODF) significantly predicted GAF at 6-month follow-up over and above initial level of global functioning and presence of a personality disorder. The group of eight defenses were identified more often (p =.068) in depressed patients who improved less than predicted by their initial functional status. The high adaptive level defense, self-observation, was identified more often in those who improved more than predicted by their initial status. Our findings support the theory of a hierarchy of defenses, and the mediating effects of specific low and high adaptive level defenses on the course of a major depressive episode. Further research should examine passive aggression, acting out, help-rejecting complaining, splitting of self-images, splitting of others' images, projective identification, projection, and devaluation in relationship to the onset, course, and treatment response of depressive disorders.