Interpersonal factors play a major role in causing and maintaining depression. This study sought to investigate how patients’ self-perceived interpersonal problems and impact messages as perceived by significant others are interrelated, change over therapy, and differentially predict process and outcome in psychotherapy of depression. For the present study, we used data from 144 outpatients suffering from major depression that were treated within a psychotherapy study. Interpersonal variables were assessed pre- and posttherapy with the self-report Inventory of Interpersonal Problems–Circumplex Scale (IIP-32; Thomas, Brähler, & Strauss, 2011) and with the informant-based Impact Message Inventory (Caspar, Berger, Fingerle, & Werner, 2016). Patients’ levels on the dimensions of Agency and Communion were calculated from both measures; their levels on Interpersonal Distress were measured with the IIP. Depressive and general symptomatology was assessed at pre-, post-, and at 3-month follow-up; patient-reported process measures were assessed during therapy. The Agency scores of IIP and IMI correlated moderately, but the Communion scores did not. IIP Communion was positively associated with the quality of the early therapeutic alliance and with the average level of cognitive–emotional processing during therapy. Whereas IIP Communion and IMI Agency increased over therapy, IIP Distress decreased. A pre–post-decrease in IIP Distress was positively associated with pre–postsymptomatic change over and above the other interpersonal variables, but pre–post-increase in IMI Agency was positively associated with symptomatic improvement from post- to 3-month follow-up. These findings suggest that significant others seem to provide important additional information about the patients’ interpersonal style.