Despite the effectiveness of endoscopic retrograde cholangiopancreatography (ERCP) for the treatment of choledocholithiasis, various complications have been described. We herein report the first case of prolonged post-ERCP jaundice due to toxicity of the contrast agent Iobitridol (®XENETIX, Guerbet, Roissy CdG Cedex, France) in a patient who underwent ERCP with sphincterectomy and common bile duct stone removal. While clinical improvement and normalization of aminotransferases and cholestatic enzymes after the procedure, an unexplained increase of direct bilirubin was noticed. A second ERCP was performed one week later, excluding possible remaining choledocholithiasis. Nevertheless, serum direct bilirubin increased further up to 15 mg/dL. Other potential causes of direct hyperbilirubinemia were ruled out and patient’s liver biopsy was compatible with drug-induced liver toxicity. Additionally, the cause-result time connection between the use of Iobitridol and bilirubin increase indicated the possibility of a toxic effect related to the repeated use of the particular contrast agent. Iobitridol, a contrast agent, can induce prolonged direct hyperbilirubinemia.