This analytic (phase II) study aimed to investigate the hypothesis that the decline in serum melanoma-inhibiting activity (MIA) levels following initiation of treatment might have prognostic value. The mean serum lactate dehydrogenase (LDH), MIA and S100 levels in patients with malignant melanoma before treatment were higher than in the control group. Patients with visceral dissemination had much higher mean serum MIA levels than patients with nodal spread only. A regression model was constructed to analyse the prognostic factors in patients with advanced stage malignant melanoma. Therapy included surgical excision or lymph node dissection, hypofractionated radiotherapy, and immunotherapy or chemotherapy. Blood samples were collected within 24 h before the initiation of systemic treatment and two or three times more at 20-28 day intervals. Overall survival was investigated by univariate analysis, and correlation with clinical factors was compared using the log-rank test. Gender, primary tumour site, surgery, radiation therapy, serum S100 levels before systemic treatment and choice of chemotherapy were not correlated with the outcome. In addition to the stage of disease, low serum LDH levels before systemic treatment and a decline in serum MIA levels following initiation of systemic treatment predicted a favourable outcome. Metastasis to visceral organs was associated with higher serum MIA levels. Persistence of high serum MIA levels despite systemic treatment predicts an unfavourable prognosis.