We have conducted a randomised phase II trial in which the activity of Letrozole plus/minus oral metronomic cyclophosphamide as primary systemic treatment has been investigated in a patient population of elderly breast cancer patients. The conclusions were that the combination of letrozole with metronomic cyclophosphamide was a very active scheme. In addition this was the first study demonstrating in vivo the antiangiogenic effect of metronomic scheduling. This study suggests that chemotherapy administered on a metronomic schedule, targeting therefore the neo-angiogenesis, could be synergistic with endocrine therapy with aromatase inhibitors.