Minocycline-induced drug rash with eosinophilia and systemic symptoms (DRESS) may have a prolonged course, especially in African and African-American patients. To determine if a prolonged course of minocycline-induced DRESS was associated with an accumulation of the culprit drug. We determined plasma and skin levels of minocycline in patients with minocycline-induced DRESS. We investigated the genetic polymorphisms of enzymes potentially involved in the detoxification of the drug, glutathione S-transferases and UDP-glucuronosyltransferases. We demonstrated the persistence of minocycline in the plasma and/or in the skin of 7 out of 9 patients with skin phototypes V-VI. As pigmented skin contains more melanin, this could promote the formation of a melanin-minocycline complex, which could explain the severe and prolonged DRESS which may occur in this subgroup of patients.