Diabetes mellitus is thought to be an autoimmune disease caused by destruction of beta cells in pancreatic islets. Insulin resistance in the peripheral tissues may also play a role. Both interleukin 2 (IL-2) and alpha interferon can enhance immune function by stimulating formation of cytolytic T cells and/or antigen expression on both normal and tumor cells. This report describes three patients with advanced malignancy who were treated with combination IL-2 and alpha interferon who had the onset or worsening of diabetes mellitus. One patient died as a result. There is evidence that interferon can increase insulin resistance and it is likely that both agents can initiate or enhance an ongoing autoimmune process. Physicians using this combination of drugs should be aware of this potential serious toxicity.