Etoposide, administered i.v. or orally, as a single agent, in 1- to 5-day courses, was found to be minimally effective in pretreated advanced breast cancer patients. Clinical data suggested an effectiveness of a chronic low-dose oral etoposide schedule, in refractory and those malignancies otherwise unresponsive to the drug. Therefore, the aim of our open-labeled, non-randomized, phase II clinical study was to investigate the efficacy and toxicity of chronic daily etoposide (50 mg/m(2) daily, for 21 consecutive days, every 28 days) as a first-line chemotherapy for metastatic breast cancer. Twenty-one advanced breast cancer patients, with or without previous adjuvant CMF chemotherapy, were included. One complete (CR) and five partial remissions (PR) were obtained in 18 patients evaluable for response. Disease stabilization was obtained in 10 patients (55%), while two patients (11%) failed to respond. Grade 3-4 hematological toxicity developed in seven out of 21 patients evaluable for toxicity or in 15 out of 96 cycles. Nonhematological toxicity was moderate. Our results showed the efficacy and relative low toxicity of a chronic oral etoposide regimen in advanced breast cancer patients. Adjuvant CMF chemotherapy did not influence the therapeutic response. Previous irradiation of the breast tended to increase the etoposide hematological toxicity.