Dermo-epidermal blistering is an uncommon presentation of adverse drug reactions. Several drugs are associated to such eruptions, but review of current knowledge does not list antiretroviral drugs. A 37-year-old Caucasian HIV-positive woman presented with a 6-week history of diffuse annular blistering affecting the trunk and limbs. Lesions appeared both on erythematous and normal-appearing skin. The patient was in treatment with antiretroviral (lamivudine + didanosine + nelfinavir) for 2 years. A history of previous adverse reactions to betalactams, nonsteroidal anti-inflammatory drugs, and a nevirapine-induced hepatitis was also referred. Histopathology showed a dermo-epidermal blister; direct immunofluorescence was positive for IgG, C3c at the basement membrane zone; enzyme-linked immunosorbent assay was positive for BP180 antigen. Oral prednisone 1 mg/kg daily for 20 days led to poor improvement. Discontinuation of the antiretrovirals was followed by a rapid healing. Blisters reappeared at first re-introduction essay 1 month later. Awareness of iatrogenic dermo-epidermal blistering is necessary to suspect the diagnosis and avoid long-term immunosuppressant treatment. Complete spontaneous recovery after withdrawal of the responsible drug and relapse at rechallenge are the main criteria for the diagnosis. Factors related to the state of the HIV infection, and/or immunodeficiency may have contributed in precipitating the reaction in the present authors' case.