Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare severe adverse drug reactions with skin blistering and keratinocyte death. Here Alcyomics has developed an in vitro skin model of TEN and has investigated its modulation by the TNF inhibitor, etanercept. Patients with SJS/TEN or maculopapular exanthem as well as serum and healthy volunteer skin samples were used in the study. Healthy skin biopsies exposed to TNFα (10 ng/mL), SJS/TEN (10% and 100% dilution), rash or healthy control sera (10% and 100% dilution), were cultured in the absence/presence of etanercept (1 µg/mL). A positive control (damage induced by Anakinra (10µg/mL) and a negative control (skin in media only) were used in all assays. Skin was incubated with or without sera and with or without etanercept for 3 days and graded for histopathological damage (grades I-IV). Skin sections were reported for the presence of necrosis or intra-epidermal damage. Skin cultured with TNFα showed grade II responses with vacuolisation of the epidermis in the presence and absence of etanercept. A grade III positive response was observed in response to SJS/TEN sera at 10x dilution with intra-epidermal damage and severe necrosis which was reduced to a grade II response in the presence of etanercept. The results demonstrate that the histopathological features of SJS/TEN can be induced by exposure to TNFα, SJS/TEN sera and rash sera, and inhibited by etanercept and suggest a putative ex vivo model of TEN with potential to be utilised as a nonclinical safety screen.