Kaposi's sarcoma (KS) is a rare angioproliferative disease associated with human herpes virus-8 (HHV8) infection. KS is frequent and aggressive in HIV-infected people, whereas the classic form (CKS) generally has an indolent course. Notably, all conventional therapies against KS have only temporary efficacy. We have previously shown that Indinavir, a HIV protease-inhibitor with direct anti-angiogenic and anti-tumor activity, is safe and effective in early-CKS patients, whereas effects are less prominent in advanced disease, probably due to the larger tumor mass. Therefore, the clinical response to Indinavir was assessed in advanced CKS patients after debulking chemotherapy. Monocentric phase-2 trial in elderly with progressive/advanced CKS treated with debulking chemotherapy and Indinavir associated, followed by a maintenance phase with Indinavir alone. Secondary endpoints included safety and KS-biomarker evaluation. All evaluable patients (22) responded to debulking therapy. Out of these, 16 entered the Indinavir maintenance phase. The overall response rate at end of maintenance was 75% (estimated median response-duration 43 months). Moreover, most responders showed further clinical improvements (lesion number/nodularity) during maintenance and post-treatment follow-up. Notably, after relapse, progressors did not require systemic KS therapy and showed clinical improvements (including disease stabilization) remaining on study. Responders also showed an immune status amelioration with a consistent B-cell increase, and positive changes of other biomarkers, including anti-HHV8 NK-activity. In advanced CKS a strategy combining Indinavir and chemotherapy is safe and associated with high and durable response rates, and it could be rapidly adopted for the clinical management of these patients.