On August 13, 2012, a nephrologist reported to the Tennessee Department of Health (TDH) three cases of unexplained thrombotic thrombocytopenic purpura (TTP), a rare but serious blood disorder characterized by microangiopathic hemolytic anemia and thrombocytopenia. The annual incidence is approximately 1 per 100,000 population. Known risk factors for TTP include infection with Shiga toxin-producing Escherichia coli (STEC) and the use of drugs, including platelet aggregation inhibitors, quinine, and cocaine. The three patients were intravenous (IV) drug users who resided in a rural county in northeast Tennessee. To identify other cases of TTP-like illness that might be associated with injection-drug use, TDH conducted a statewide investigation. By the end of October, a total of 15 such cases had been reported; none were fatal. A case-control study was conducted, and investigators determined that the cases of TTP-like illness were associated with dissolving and injecting tablets of Opana ER (Endo Pharmaceuticals), a recently reformulated extended-release form of oxymorphone (an opioid pain reliever) intended for oral administration. Fourteen of the 15 patients reported injecting reformulated Opana ER. Seven of the 15 were treated for sepsis in addition to TTP-like illness. Twelve patients reported chronic hepatitis C or had positive test results for anti-HCV antibody. Health-care providers who prescribe Opana ER and pharmacists who dispense it should inform patients of the risks from the drug when used other than as prescribed. Health-care providers should ask patients with TTP-like illness of unknown etiology about any IV drug abuse. Suspected cases can be reported to public health officials.