BACKGROUND Multiple drug hypersensitivity (MDH) was first described in 1989 by Sullivan et al. as drug allergies to two or more chemically different drugs. So far, the diagnosis of MDH was associated almost exclusively with antibiotics and was defined based on history alone. OBJECTIVE The objective of this study was to prove MDH by two independent tests, namely patch (PT) and lymphocyte transformation (LTT) tests. METHODS Here we present 7 patients matching the definition of a MDH which were documented by positive LTT as well as PT to different drugs. RESULTS Three of the 7 patients developed sensitization to the different compounds during the same treatment period and had one longer-lasting allergic reaction. For another 4 patients sensitization to the different drugs occurred at distinct time points. CONCLUSIONS Our data support the concept of a MDH syndrome. The multiple sensitizations can be proven by skin and in vitro tests. We propose two subtypes of MDH: MDH, which develops against different drugs given simultaneously, and a second subtype, where the sensitizations develop sequentially. Antibiotics are often involved, but we also found sensitization to antiepileptics, hypnotics, antidepressants, local anesthetics, corticosteroids and other drug classes.