Twenty-seven women with metastatic breast cancer (at least one site of measurable disease) entered a phase II study of chronic oral etoposide (50 mg/m2/day x 21 days, given every 4 weeks). To date, 23 patients are evaluable for response and toxicity. All patients had received prior chemotherapy (adjuvant therapy, one patient; adjuvant plus chemotherapy for metastases, six patients; chemotherapy for metastases, 16 patients). Thirteen patients had previously received anthracyclines, and 10 had also received prior hormonal therapy. Of the 23 evaluable patients, one obtained a complete response and six achieved partial responses (objective response rate 30.4%, 95% confidence interval, 13 to 53%). Responses were seen in lymph nodes (three of eight sites), skin and soft tissue (five of seven), lung (two of six), lytic lesions of the bone (one of three), and liver (1 of 12). The median duration of responses was 6 months (range, 1+ to 8). The main toxic side-effects were leukopenia (74% of patients), thrombocytopenia (22%), and anemia (69.5%). Myelosuppression in four patients (17%) necessitated a 25% dose reduction. Other toxicities included alopecia (83%), mucositis (52%), and emesis (35%). Chronic oral etoposide appears to be an active regimen in metastatic breast cancer patients previously exposed to chemotherapy.