Telaprevir is a specific inhibitor of the hepatitis C (HCV) serine protease 3. Cutaneous side effects have been reported with telaprevir. Drug reaction with eosinophilia and systemic symptoms (DRE SS) is a rare yet severe adverse drug-induced reaction characterized by exfoliative dermatitis and maculopapular rash, lymphadenopathy, fever, eosinophilia, leukocytosis, and myriad internal organ involvement. We report a case of DRE SS due to telaprevir. A 64-year-old Caucasian man with chronic hepatitis C developed a progressive diffuse, painful maculopapular exanthema with fever, facial edema, lymphadenopathy at week 11 of chronic hepatitis C therapy with telaprevir, Peg-Interferon alfa-2a, and ribavirin. He had no exposures to any other medications. He presented an eosinophilia (up to 6.29 X 10(9) cells/L), skin biopsy was consistent with a drug reaction. The HCV treatment was stopped and methylprednisolone 0.75 mg/kg/day was started. Cutaneous and systemic symptoms had a rapid resolution in few days. Telaprevir can activate severe skin reactions that can mimic an infectious disease, therefore early diagnosis and discontinuation of chronic hepatitis C treatment is mandatory.