Enfortumab Vedotin (EV) is an antibody-drug conjugate for metastatic urothelial carcinoma. Hyperglycemia and diabetic ketoacidosis (DKA) have been reported in patients using EV. The incidence increases with higher BMI. The one case report available on the association between EV and DKA resulted in development of multiorgan failure and death. This case, however, describes a positive outcome with recovery from DKA. We present a case of a 59 year-old Caucasian woman with morbid obesity, prediabetes and recurrent metastatic urothelial cell carcinoma who presented with hyperglycemia after 2 doses of EV. Labs were indicative of DKA without an infectious etiology. She was admitted to the ICU for intravenous insulin drip treatment. Hyperglycemia and ketosis persisted despite using a maximum insulin drip rate of 60 units/hour. Starvation ketosis was a factor, so a diet was started. On day 2, NPH insulin and prandial lispro were added along with the insulin drip, resulting in a total daily insulin dose of 1660 units. Nevertheless, hyperglycemia persisted. U-500 regular insulin was initiated and by day 4, the patient received a total of 2940 units of insulin in one day with normalized serum ketones. Insulin drip requirements decreased with blood glucose controlled solely on subcutaneous insulin. She remained euglycemic, so U-500 insulin was switched to daily glargine. Eventually, she was off all insulin and maintained blood glucose below 130 mg/dL. Work up for insulin resistance included a C-peptide of 42.6 ng/mL (normal 1.1-4.4) with glucose of 230 mg/dL, negative glutamic acid decarboxylase 65 and insulin antibodies, and a glucagon level of 213 pg/mL (normal ≤80) with glucose of 220 mg/dL. Although the mechanism by which EV causes hyperglycemia is not known, this case illustrates that hyperglycemia was due to severe insulin resistance associated with EV. Understanding this, along with glycemic effects of targeted therapies with Vedotin are necessary to investigate the causal mechanism and treatment for EV related hyperglycemia/DKA. Disclosure A.Elahi: None. J.Duron: None. T.Porter: None.