The objective of this phase II study was to evaluate the activity and toxicity of oral etoposide (50 mg/m2 daily for 21 days in 28-day cycles) in patients with heavily pretreated metastatic breast cancer. Thirty patients were entered into the study; all had clinical or radiologic evidence of disease progression, median age was 51 years, and the majority of patients (82%) had a Zubrod performance status equal to or lower than 1 and a median of 3 disease sites. All patients had received chemotherapy, and more than 80% had received 3 or more regimens. More than 70% of the patients had received taxanes as one of their previous therapies. Twenty-four and 28 patients were evaluable for tumor response and toxicity, respectively. One partial response was seen (<4%), and seven patients (25%) demonstrated stable disease with a median duration of four months. There was significant hematologic toxicity. In two patients therapy had to be stopped because of excessive toxicity, and five patients required hospitalization for neutropenic fever. Overall, 57% of patients experienced grade 2 or higher degree of neutropenia including two patients with grade 4 toxicity. Seventeen percent of patients developed grade 2 or greater thrombocytopenia, including one patient who experienced grade 4 toxicity, and 71% of the patients had grade 2 or more severe anemia including two patients with grade 4 toxicity. Oral etoposide has limited activity as third- or fourth-line agent and produces significant hematologic toxicity in patients with heavily pretreated metastatic breast cancer.