Drug reaction with eosinophlia and systemic symptoms (DRESS) syndrome describes a severe medication-induced adverse reaction, which shows skin, blood and solid-organ features. Up to 50 drugs have been described to cause DRESS. The main responsible drugs are carbamazepine and allopurinol. There are no previous reports associated with acenocoumarol. A 85-year-old white male, who was treated with acenocoumarol for the prevention of venous thromboembolism due to atrial fibrillation, presented 6 weeks later a maculopapular exanthema of the trunk and limbs as well as purple lesions and blisters on distal parts of his legs. Elevated creatinine, glucose, urea, International Normalized Ratio, gamma-glutamyl-transpeptidase (GGT) and eosinophilia levels were observed. Acenocoumarol was removed and enoxaparine, systemic corticosteroids, antihistamines were used as treatment with a favorable clinical evolution: 1 month later, the skin lesions had disappeared and laboratory parameters were normalized. Patch tests with warfarin and dabigatran were carried out. Two simple-blind, placebo-controlled oral challenges with warfarin and dabigatran were performed. Patch tests were negative, and single-blind, placebo-controlled oral challenges with warfarin and dabigatran were achieved without immediate or delayed reactions. We firstly describe a DRESS syndrome induced by acenocoumarol. Patch test was useful to assess alternative therapies. Tolerance to other anticoagulants (warfarin and dabigatran) was demonstrated.