This paper describes the rationale and treatment principles of a mother-infant unit for severely depressed mothers and their infants in Flanders (Belgium). The unit integrates systemic, psychodynamic, and cognitive behavioral treatment approaches, and aims at improvements on three levels: (1) improving mood and interpersonal relationships in depressed mothers, (2) fostering a positive mother infant relationship, and (3) establishing a supportive environment outside the treatment setting for both mother and infant. In addition, we present preliminary data of a 3.5-year naturalistic follow-up study of postpartum depressed mothers (n = 41) admitted at this mother-infant unit between April 2003 and April 2005. Results showed that at 3.5-year follow-up a considerable subgroup of mothers (61%) were functioning relatively well, as indicated by low levels of depressive symptoms, anxiety and anger, negative affect, and relatively high levels of positive affect. Yet, in line with other studies, a relatively large subgroup of mothers (39%) continued to suffer from (severe) depression during follow-up. Using a Life History Calendar method, it was found that, compared to currently nondepressed mothers, mothers who were depressed at follow-up did not have more depressive episodes but had longer depressive episodes, received more psychotherapy after hospitalization, and experienced more negative life events during the 3.5-year follow-up period. Implications of these findings for future research and intervention strategies in postpartum depression are discussed.