Interferon-alpha-2b (IFNalpha2b) is the only effective adjuvant therapy for melanoma patients at high risk of recurrence that has been approved by regulatory authorities worldwide. However, IFN toxicities increase the risk of poor treatment compliance and impair the potential for benefit from this agent. A review of the literature demonstrated little recent attention to supportive care in the management of IFN toxicities. An international group of experts with extensive personal experience in the use of IFNs worked together to develop practical guidelines for the use of IFNs. Practical recommendations were developed for patient education on the use of IFN; initial patient assessment and monitoring, including contraindications to the use of IFN, monitoring and managing adverse events, and IFN dose modification and discontinuation; IFN injection procedures; treatment of elderly patients; and use during pregnancy and nursing. Successful adjuvant therapy of melanoma with high-dose IFN requires close compliance with the treatment regimen. Recommendations for the recognition and management of adverse events are designed to enable more patients to complete the full planned course of treatment.