Optimal first-line chemotherapy for metastatic breast cancer (MBC) is challenging, particularly in patients previously treated with (neo) adjuvant anthracyclines/taxanes. Based on preclinical synergy with mitomycin C (MMC) and capecitabine in human tumor xenografts, we conducted a phase II study of first-line capecitabine and MMC in MBC. Patients received 3-weekly chemotherapy comprising MMC 8 mg/m² day 1 and capecitabine 1000 mg/m² twice daily, days 1-14. Combination chemotherapy was administered for a maximum six cycles, single-agent capecitabine could be continued until progressive disease or unacceptable toxicity. Thirty patients were included, objective response rate was 65.5%. After a median follow-up of 18.5 months, median time to progression was 8.5 months and median overall survival was 29.8 months. The main adverse events were thrombocytopenia, pneumonitis and hemolytic uremic syndrome. Our data suggest that first-line capecitabine and MMC has good antitumor activity in MBC, but is associated with MMC-specific toxicity.