We report a patient with type 2 diabetes mellitus who, while treated with the antitumor necrosis factor-alpha blocking agent etanercept for severe plaque psoriasis, experienced persistent hypoglycemia requiring the lowering and eventual elimination of his previous insulin regimen. After 20 months of therapy on etanercept, his plaque psoriasis markedly improved, whereas both his fasting blood sugars and glycosylated hemoglobin A(1c) decreased. Hypoglycemia can be a serious side effect of etanercept in patients already on antidiabetic medications known to cause hypoglycemia, such as sulfonylureas, meglitinides, and insulin. Thus, it is important for dermatologists treating patients with diabetes and antitumor necrosis factor-alpha agents for psoriasis to be aware of potential hypoglycemia and to adjust antidiabetes therapy accordingly.