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Capecitabine and cyclophosphamide are active in patients with advanced breast cancer, have non-overlapping toxic effects and synergy pre-clinically. We explored the efficacy and toxic effect of an all-oral combination of capecitabine with cyclophosphamide versus capecitabine alone in a multicentre, randomized, phase II study.Patients with locally advanced or metastatic breast cancer were randomized to treatment with capecitabine given continuously (666 mg/m2 b.i.d. days 1–28) alone (C) or with oral cyclophosphamide (100 mg/m2 days 1–14 of a 28-day cycle) (CCy) for up to six cycles.Eighty-two patients were randomized. There was no complete response. The proportions with partial response were 36% on C and 44% on CCy, a difference of 7.9% [95% confidence interval (CI) −13.4 to 29.1]. Significant toxic effect was uncommon: grade ≥3 diarrhoea in 4 (10%) versus 1 (3%) patients; grade ≥3 fatigue in 2 (5%) versus 5 patients (13%) and grade ≥2 hand-foot syndrome in 7 (17%) versus 11 (28%) patients receiving C versus CCy, respectively. Median progression-free survival was 3.1 months on C and 6.9 months on CCy, not significantly different statistically. There was no difference in overall survival.The difference in tumour response suggests a reasonable chance that CCy is superior to C alone.