Background: DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) is an uncommon severe systemic hypersensitivity drug reaction. All antituberculotic drugs have a risk to induce drug hypersensitivity syndrome of which Rifampicin is the most prevalent. Case presentation: In this report, we describe a clinical case of 62-year-old man who experienced the typical clinical course of DRESS syndrome caused by Rifampicin. Clinical manifestation (fever, facial edema, widespread skin lesions, internal organ involvement, and haematological abnormalities) occurred within 4 weeks after empirical treatment of prosthetic valve endocarditis. Symptoms improved after discontinuation of antibiotics and a culprit drug was confirmed by allergological skin patch testing. Conclusion: Due to possibility of various systemic manifestations, diagnosis of DRESS syndrome is often overlooked but it should be considered for its severe complications.