Capecitabine (Xeloda, X) and cyclophosphamide (C) can be given orally and they have synergistic effects with nonoverlapping toxicities in preclinical studies. A phase I study of the XC combination therapy was conducted in patients with metastatic breast cancer (MBC) and determined the recommended dose and schedule of 1657 mg/m/day capecitabine and 65 mg/m/day cyclophosphamide given orally for 2 weeks at a 3-week interval. A phase II study of the oral XC regimen was then conducted. This study enrolled patients with HER2-negative MBC who were earlier treated with anthracyclines. XC was given at the recommended doses on a 3-week schedule for at least six courses unless disease progression or unacceptable toxicities occurred. The primary endpoint was the response rate. Progression-free survival, overall survival, and adverse events were investigated as secondary endpoints. Forty-eight patients with the median age of 58 (range 32-72 years) years were registered. Three patients withdrew by choice before starting the treatment. A complete response was obtained in two of the 45 evaluable patients, and partial response in 14, resulting in an overall response rate of 35.6%. The median progression-free survival and overall survival were 199 (115-231) days and 677 (437 approximately ) days, respectively. Grade 3 neutropenia and leukopenia developed in 11%, and that of anemia and thrombocytopenia in 2% patients. Nonhematological toxicities were mild. Hand--foot syndrome was observed in 14 patients but no one had grade 3-4 toxicity. Oral XC combination is effective with acceptable toxicities in patients with MBC.