Opana ER (oxymorphone) is an opioid drug available throughout the United States, and intravenous abuse of the crushed oral formulation has been associated with drug-induced thrombotic microangiopathy. In this abstract, we describe two young patients who lived together and used Opana ER intravenously. Both presented with microangiopathic hemolytic anemia that mimicked thrombotic thrombocytopenic purpura (TTP). Treating this condition poses a clinical challenge, as it is difficult to distinguish it from TTP. The role for plasma exchange is not clear but can be used while awaiting the results of the ADAMTS-13 activity, but ultimately supportive care with drug discontinuation is the recommended therapy of choice. Patients should be counseled against Opana ER's intravenous use, and users should be offered drug rehabilitation therapy.