Introduction: Before the arrival of highly active antiretroviral therapy (HAART), interferon α has been used successfully to treat AIDS-related Kaposi's sarcoma (KS). Peginterferon-α (pegIFN-α) may still be used successfully in refractory KS. Case: Peginterferon-α and ribavirin (RBV) were initiated to treat hepatitis C virus (HCV) infection in an HIV-infected patient with high CD4 counts having discontinued antiretroviral therapy (ART). He developed disseminated KS 6 months after HCV treatment began. Beginning of ART, discontinuation of pegIFN/RBV, and 2 cycles of doxorubicine were necessary to treat KS. Discussion: Despite its activity on KS, thanks to its antiviral and antiangiogenic properties, PegIFN was unable to prevent the occurrence of severe KS. The absence of ART, despite high CD4 counts, and interferon-induced lymphopenia probably triggered the occurrence of KS in this patient.