Using mixed effects models, the authors examined the effects of chronic stress, adverse parent-child relationships, and family history on the 7.5-year course of dysthymic disorder. Participants included 97 outpatients with early-onset dysthymia who were assessed with semistructured interviews at baseline and 3 additional times at 30-month intervals for 7.5 years. Results indicated that higher levels of chronic stress 6 months prior to each follow-up predicted greater depression severity at follow-up, controlling for depression severity at the start of the chronic stress assessment. In addition, adverse parent-child relationships and family history of dysthymic disorder moderated this association. For patients with poorer parent-child relationships, chronic stress was associated with increased depression severity at follow-up, whereas patients with a higher familial loading for dysthymic disorder were less responsive to chronic stress over time.