To date, no standard adjuvant therapy have increased overall survival in patients with malignant melanoma (MM). The effect of interferon alpha as a single agent or in combination has been widely explored in clinical trials. Critical reading of the major international randomised trials showed that response to interferon (IFN) in terms of improvement of overall survival (OS) may not be strictly correlated with the used dosage and that duration of therapy may impact disease-free survival (DFS) but not OS. Patients' heterogeneity could be an explanation for the discordant data of the international literature. Indeed, majority of these studies started in late 1980s or early 1990s, when accurate staging procedure were not available yet. The adequate surgical treatment should be considered as an independent variable in the analysis of MM adjuvant protocols. Considering the treatment cost, which is the main goal: DFS, OS or quality of life? Answering these questions is difficult, but some considerations must be taken to put order in this field. Putting together data from all different studies, IFN therapy seems to protect MM patients from recurrences during the entire treatment period and a prolonged IFN therapy seems to improve DFS. The only positive result on OS was demonstrated for high-dose IFN (HD-IFN) in a single study (presenting a relatively short follow-up median) and not confirmed in a subsequent study from the same authors. Considering that low-dose interferon (LD-IFN) is tolerated much better than HD-IFN (about 10% versus more than 70% of cases with grade 3-4 toxicity, respectively), a prolonged LD-IFN (more than 2 years) may represent a reasonable opportunity for MM patients, also considering its advantageous cost-effectiveness. Conversely, considering the improvement of OS as the main target of MM adjuvant therapy, the "wait and watch" attitude remains the only approach to be pursued at present. It is a physician's choice.