The study examined the ability of Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF) substantive scales to predict depressive symptoms in a psychiatric inpatient setting. The indirect effect of patient-rated alliance with their treatment team on these relationships was also investigated. Participants included 678 (52.5% female, 97.1% White) inpatients diagnosed with a mood disorder. MMPI-2-RF scales, Patient Health Questionnaire (PHQ-9) at intake and discharge, and Working Alliance Inventory-Short at discharge were used to test study hypotheses regarding MMPI-2-RF predictive utility and the influence of alliance. Jacobson and Truax’s (1991) reliable change index (RCI) was calculated to identify those who did (74% of the sample) and did not (24%) make reliable and clinically significant depressive symptom change, and the predictive utility of MMPI-2-RF scores in distinguishing these groups was examined. MMPI-2-RF scales assessing internalizing and somatic dysfunction accounted for an additional 2% to 8% of the variance in depressive symptoms reported at discharge, above and beyond depressive symptoms reported at intake. Somatic scales were also able to differentiate groups based on clinically significant change on the PHQ-9 (small-sized effect). The relationship between MMPI-2-RF scales and depressive symptoms at discharge was indirect through alliance in 64% of models. Clinical implications are discussed.