Previous short-term studies evaluating U-500 insulin have reported improvements in glycemic control but with significant weight gain. This study was performed to examine the glycemic durability of U-500 insulin in highly insulin resistant subjects, and to determine if weight gain was continuous with use. Patients using U-500 insulin provided consent for chart reviews for up to 3 years prior to and 3 years after use of U-500 insulin. Charts were reviewed for physical and metabolic data from 53 subjects using U-500 insulin of which 20 used U-500 insulin for 3 years. Use of U-500 insulin led to an approximate 1% decrease in HbA1c within 3–6 months of use which was sustained for up to 3 years. Patients required increased insulin doses (by ~80%) over the first 6–12 months with a corresponding weight gain (~10 lbs) and a spike in hypoglycemia symptoms, but then insulin doses and body weight, as well as glycemic control and hypoglycemic symptoms, stabilized over subsequent follow up. Use of U-500 insulin in a clinical diabetes practice leads to sustained improvements in glycemic control following a period of insulin titration and weight gain. Despite the weight gain, glycemic control was sustained for up to 3 years.