Our objective was to study the clinical and management differences between primary and interferon (IFN)-induced depressive disorders in malignant melanoma patients visited by the consultation-liaison team during a two year period. This was a prospective study of 31 patients with malignant melanoma treated with IFN-alpha in a general teaching hospital. Clinical, psychiatric variables and DSM-IV-TR diagnosis were analyzed. The Clinical Global Impression Severity (CGI-S) and Improvement (CGI-I) of illness scales were administered at the time of consultation and at the end of hospitalization. The main diagnoses were depressive adjustment disorders in 14 patients (45.16%) followed by interferon-induced depressive disorders in 6 (19.36%). In patients with adjustment disorders, melanoma stage was significantly more advanced than in those with interferon-induced depressive disorder (p = 0.019). The latter scored higher in the CGI-S scale (p = 0.044) and in the CGI-I scale (p = 0.029). The interferon-induced depressive disorders, except one who required a reduction of IFN-alpha-2b dose, were successfully treated with antidepressant drugs. Clinical management and antidepressant treatment allowed the continuation of interferon therapy in malignant melanoma patients. Interferon-induced depression occurred in a few patients, which in turn were the most severe. Adjustment depressive disorder was the most common psychiatric diagnosis.