Background: Changes in hemoglobin A1c (A1C), weight, and total daily insulin dose (TDD) were investigated following initiation of insulin U-500 (U500) alone or as part of a basal/bolus insulin (BBI) regimen. Subjects and Methods: Records of patients with type 2 diabetes who were prescribed U500 were retrospectively reviewed. Logistic regression analysis was used to investigate relationships between changes in A1C and use of U500 alone or as BBI. Results: Twelve patients were identified as using U500 alone (n = 2) or in combination with long-acting (LAI) (n = 7) or rapidacting (RAI) (n = 3) insulin. Reductions in A1C (9.5% at baseline vs. 7.7% at 6-9 months, P < 0.0001) and increases in weight (128.8 -32.7 vs. 131.5 -31.3 kg, P < 0.014) and TDD (260 -111 to 333 -106 units/day, P < 0.0002) were observed. Concurrent use of LAI or RAI with U500 did not predict improvements in A1C. Conclusions: U500 resulted in improvements in A1C and weight gain and increased TDD when used alone or as part of combination insulin therapy. Further investigations to define the optimal use of U500 are recommended.