Metastatic breast cancer (MBC) patients derive benefit from chemotherapy, but options become limited after several prior chemotherapeutic regimens. Oral etoposide (VP-16) has previously been found to be clinically active in MBC patients in phase II trials. However, with increasing availability of other drugs, etoposide use has declined in spite of its unfavorable toxicity profile probably being overestimated. We therefore evaluated the clinical benefit and safety of oral etoposide in a population of MBC patients who had failed multiple regimens of currently used therapies. Sixty-six patients with MBC previously treated with a median of eight (range 2–13) regimens of therapy were eligible for the study. Patients received 50 mg/day oral etoposide in 20-day cycles with 1-week of rest. All patients were evaluated for clinical benefit (clinical benefit rate [CBR], complete response, partial response, and disease stabilization >24 weeks), progression-free survival (PFS), overall survival (OS), and toxicities. Median PFS was 4 months, CBR was 18% (overall response rate 4%), and median OS from the start of treatment was 11 months. Little clinically significant or high-grade toxicity were observed. No patients withdrew from treatment due to etoposide-induced toxicity. The favorable clinical response, low toxicity, and low cost of the drug suggest that etoposide is a viable option for patients with heavily pretreated MBC.