Hyperglycemia secondary to total parenteral nutrition (TPN) is reported in adults. In addition, insulin resistance and type 2 diabetes as late consequences of hematopoietic stem cell transplantation (HSCT) are well described. Both situations are generally manageable with traditional insulin dosing. We present two children who developed severe insulin resistance requiring intravenous insulin therapy at doses up to 13 units/kg/h. Both children were on TPN after undergoing HSCT for hemophagocytic syndrome. We believe that our report will alert physicians to such a condition and help with early recognition that is a key to successful intervention. These cases aim to increase awareness and stimulate research to unravel the associated underling mechanisms.