Objective: This study investigated associations between couples’ interpersonal behavior, depressive symptoms, and relationship distress over the course of couple psychotherapy. Method: After every other session of Integrative Systemic Therapy (M = 13 sessions), N = 100 individuals within 50 couples rated their in-session affiliation and autonomy behavior using the circumplex-based Structural Analysis of Social Behavior Intrex. Concurrent and prospective associations of interpersonal behavior with depressive symptoms and relationship distress were evaluated via multivariate multilevel modeling using the Actor-Partner Interdependence Model. Results: An individual’s hostility, as well as the partner’s hostility, positively predicted an individual’s concurrent depressive symptoms and relationship distress, as well as his or her relationship distress at the following session. Partner hostility during one session predicted an individual’s subsequent depressive symptoms. During sessions in which individuals controlled the partner, and separated themselves from the partner, they reported more concurrent depressive symptoms and relationship distress, and more subsequent relationship distress. When partners separated themselves, individuals reported more concurrent depressive symptoms and relationship distress, and more subsequent relationship distress. Conclusions: Results underscore the importance of couples’ in-session affiliation and autonomy behavior in the treatment of depressive symptoms and relationship distress within couple therapy.