A 72-year-old man was diagnosed as having cirrhosis of the liver in 1993 and diabetes mellitus in 1996. He was prescribed two doses of mixed human insulin (22 units at breakfast and 10 units at dinner) to maintain good glycemic control. However, the patient noted several diabetic symptoms, and his plasma glucose level increased to above 28 mmol/l in October 2001. Despite a decrease in his total insulin dose, the plasma glucose level did not respond. After admission to our divisionis, his prescription was changed to four doses per day of regular and NPH insulin (a total of 190 units per day), but his plasma glucose level remained at over 22 mmol/l. Investigations at the time of admission revealed a remarkably high titer of insulin antibody (96%). When we changed his insulin from regular human insulin to Lispro, his plasma glucose level improved. After three days, his plasma glucose level was around 5.5 mmol/l, and he sometimes felt hypoglycemic in the early morning. Eventually, he no longer needed NPH insulin and his dosage was reduced to only three doses per day of Lispro (a total of 120 units per day). Examination of the specific antibodies for both human insulin and Lispro suggested that some of his insulin antibodies had reacted with an epitope where two amino acids were replaced in the structure of insulin.