Combination antiretroviral therapy (cART) reduced the incidence of Kaposi's Sarcoma (KS), mainly mediated by the suppression of HIV replication and the recovery of the immune system. The effect of specific classes of antiretrovirals on KS remains unclear. However, both in vitro and clinical studies provided evidences that protease inhibitors (PI) can inhibit Human Herpesvirus 8 (HHV-8) replication and reduce KS risk and progression. Moreover, relapses of KS in HIV-infected patients switching from a PI to a non-nucleoside reverse transcriptase inhibitor-based cART have been reported. We describe here the case of a patient who experienced a relapse of KS and a rebound of HHV-8 viremia two months after switching from a PI to an integrase inhibitor-based cART.