Outcome in melanoma patients with advanced disease is poor and systemic treatment seems to benefit only a subset of patients. Predictive markers identifying these patients are currently not available. Early studies showed an association of immune-related side effects such as vitiligo and autoimmune thyroiditis with response to IL-2 or IFN alpha treatment. However, conflicting data have been reported as well, mentioning the effect of a higher rate of immune-related toxicities during prolonged administration of the drug in responders. The review discusses the prognostic significance of autoimmunity during various forms of immunotherapy and stresses the importance of correcting for guarantee-time bias. In addition, other immune-related factors which have been associated with melanoma prognosis such as, CRP, white blood cell count, absolute lymphocyte count and human leukocyte antigen will be reviewed as well. A better understanding of the immune system and the host-tumor interactions should ultimately lead to more effective treatment. A major challenge expected to be addressed in future is proving ways to uncouple tumor immunity from autoimmunity. (C) 2011 Published by Elsevier B.V. on behalf of Federation of European Biochemical Societies.