Insulin requirements vary among patients with diabetes due to insulin resistance. For patients whose glycemic goals are not achieved with basal and bolus rapid-acting insulin analog regimens (IBB) owing to insulin resistance, we assigned treatment with basal and thrice-daily biphasic insulin lispro 50/50 (IBB-50). The present study compared the effect of thrice-daily lispro 50/50 combined with insulin glargine in patients with insulin-resistant type 2 diabetes mellitus, was conducted at one medical center. Thirty-eight patients with type 2 diabetes (aged 30–75 years, using stable insulin dose for last 3 months, HbA1c>8.5%) participated in this clinical observational study. The study was continued twelve weeks. Patients who had been treated with stable basal insulin glargine with a prandial bolus rapid-acting insulin analog medication with metformin were switched to basal insulin glargine and thrice-daily biphasic insulin lispro 50/50 and metformin. The patients had a mean age of 56.9 ± 7.0 years, diabetes duration of 15.7 ± 8.3 years, and an HbA1c of 10.7 ± 1.3%. The preprandial rapid-acting insulin analogs were switched to thrice-daily biphasic insulin lispro 50/50. After 12 weeks, fasting and postprandial plasma glucose and HbA1c were significantly reduced. No serious adverse drug reactions, major or nocturnal hypoglycemia were reported. Our study results suggest that the IBB-50 therapy may be necessary to improve glycemic control if patients with type 2 diabetes have high total daily insulin requirements that are inadequately controlled by basal-bolus insulin regimens.