Pegylated interferon alfa is a pegylated formulation of recombinant human interferon (IFN) conjugated with polyethylene-glycol (PEG). The major advantages of this formulation, compared to standard IFN, is a prolonged half-life which allows for once-weekly injection. Its antiviral efficacy in association with ribavirin as a new standard treatment of chronic hepatitis C has been recently documented. Efficacy of PEG-IFN in the therapy of HIV infection is currently being evaluated in prospective pilot studies. We describe herein the first observation of cutaneous necrosis at the sites of PEG-IFN injection in an HIV-infected patient. A 50-year-old man, HIV infected, was treated with antiretroviral bitherapy combining zidovudine and didanosine for 30 months. Weekly subcutaneous injections of PEG-IFN-alpha-2b were started at a dose of 1.5 microg/kg. Nine months later, two successive necrotizing cutaneous lesions developed at the site of injection. The cutaneous ulcerations slowly healed under local therapy without interruption or dose modification of the PEG-IFN. We review the literature on previously reported cases of cutaneous necrosis following standard or pegylated IFN-alpha injection and discuss the different pathophysiological mechanisms that might be involved.