OBJECTIVE Liposomal anthracyclines and paclitaxel are considered the best available cytotoxic therapies for Kaposi's sarcoma (KS), but relapse is common. To identify new interventions for relapsed or progressive KS, a phase II study of low-dose etoposide to assess its toxicity and efficacy was conducted. METHODS Thirty-six patients with high-risk KS were treated with oral etoposide 50 mg/d for 7 consecutive days of every 2-week cycle. All patients' disease had relapsed or progressed after prior combination chemotherapy or anthracycline therapy. For patients without a complete or partial response after two cycles of therapy and no toxicity greater than grade 2, the dose of etoposide was escalated to 100 mg/d orally on days 1 to 7 of each 14-day cycle. Treatment-related and disease-specific quality of life was evaluated using patient reports on the General Health Self-Assessment Form and a KS-specific measure. RESULTS One patient achieved a complete response, 12 patients had a partial response (overall response rate, 36.1%), and stable disease was observed in 12 patients (33.3%). Tumor responses were seen in all disease sites. Fourteen patients had their dose escalated, of whom five responded. The median time to response was 17.7 weeks; the median duration of response was 25 weeks. The most frequent hematologic abnormality was neutropenia, which was grade 4 in seven patients and grade 3 in six. Opportunistic infections occurred in eight patients during the treatment period. Both response to treatment and toxicity influenced patient-reported quality of life. CONCLUSIONS We conclude that low-dose oral etoposide at a dose of 50 mg/d is safe and effective for the treatment of refractory or progressed AIDS-related KS and has an overall positive effect on the quality of life of responding patients.