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The purpose of the present study was to evaluate the incidence, spectrum and extent of psychiatric symptoms in patients with malignant melanoma (MM) before and during adjuvant treatment with interferon-alpha (IFN-α). 850 patients with cutaneous MM of ≥1.5 mm tumor thickness received standard low-dose IFN-α 2a in this prospective multicenter trial of the Dermatologic Cooperative Oncology Group (DeCOG). Psychiatric symptoms were evaluated at baseline and after 3, 6, and 12 months with the Beck Depression Inventory (BDI) and the Symptom Check List 90-Revised (SCL 90-R). In all, 282 patients completed all questionnaires. Mean BDI depression scores increased significantly during the first 6 months of IFN-α treatment (P ≤0.001), followed by a mild but not significant decrease. Also mean SCL 90-R scores increased significantly during the first 3 months of adjuvant treatment with IFN-α (P≤0.001) and remained elevated until month 12 (P≤0.001). Only 5% developed BDI scores >10, indicating a clinically significant depressive syndrome and only 1.4% reached a BDI score ≥18, indicating a moderate to severe depressive syndrome. Patients, who dropped-out early from psychiatric reasons, had significantly increased BDI and SCL-90R scores at baseline. Women scored higher in both scales before and during treatment if compared with men. In conclusion, adjuvant treatment with IFN-α was associated with a significant increase of BDI- and SCL 90-R scores. A higher pretreatment depression score was found to be a risk factor for an early drop-out during therapy. Pretreatment screening and an interdisciplinary care of the patients is recommended.