Oxymorphone is a semisynthetic extended release opiate used to treat moderate to severe chronic pain. The Food and Drug Administration approved the oral form of oxymorphone available as Opana and Opana ER (extended release) since 2006. The Food and Drug Administration and the Centers for Disease Control and Prevention issued warning against intravenous use of Opana ER. We are presenting a case report of a 37-year-old female with a history of active intravenous drug abuse who presented to our hospital with acute kidney injury. Urinalysis showed red blood cell sediments, many dysmorphic red blood cell casts along with nephrotic range proteinuria of 12 g/deal per day. Kidney biopsy showed microscopic thrombotic microangiopathy (TMA) involving glomeruli and vessels. Further workup was undertaken for TMA, and apart from mildly elevated lactate dehydrogenase of 380 (normal <243), active hepatitis C, and slightly low ADAMTS-13 (55%), there was no other laboratory evidence of TMA. On literature search, we found that intravenous injection of chronic Opana ER has been reported to cause TMA resulting in chronic kidney disease. Our patient also admitted to use of intravenous Opana ER abuse for the past 5 years. She had a normal platelet count and an absence of schistocytes, which makes it an atypical presentation of TMA resulting in chronic kidney disease in an opiate user. We strongly urge physicians to avoid prescribing opiates for chronic pain, especially Opana ER, which if injected intravenously for recreational purposes can lead to serious side effects like TMA. Treatment is mainly supportive and avoidance of drug in future.