The degree to which interferon (IFN) alpha-2b offers real clinical benefits in the adjuvant therapy of melanoma at high risk of recurrence is a subject of debate. This, together with questions over optimal treatment scheme and concerns over toxicity, has limited its clinical use. On the basis of a review of the literature, an Italian Expert Panel has made practical recommendations for a consistent approach in the use of IFN. Although it is clear that more research into predictive factors to identify patients most likely to benefit from adjuvant IFN therapy is required, IFN remains the only currently available adjuvant option for melanoma. Based on meta-analyses of clinical trials, there is clear evidence that treatment with IFN is beneficial with regard to overall and recurrence-free survival (RFS). As such, IFN should be offered to patients who are at high risk of recurrence. Specific recommendations with regard to disease stage are provided.