Background: The presence of disseminated tumor cells (DTCs) in bone marrow of patients with early breast cancer (EBC) has been correlated with increased risk of metastatic disease or locoregional relapse. Zoledronic acid (ZOL) treatment has reduced DTCs in the bone marrow of patients with EBC in several studies. This controlled study sought to confirm these observations. Patients and methods: Patients with EBC and DTC-positive bone marrow were randomized (N = 96) to treatment with ZOL plus adjuvant systemic therapy or adjuvant systemic therapy alone. The change in DTC numbers at 12 months versus baseline was measured. Results: DTC-positive patients treated with ZOL were more likely to become DTC-negative after 12 months of treatment compared with the controls (67% versus 35%; P = 0.009). At 12 months, DTC counts decreased to a mean of 0.5 ± 0.8 DTCs in the ZOL group and to 0.9 ± 0.8 DTCs in the control group. In addition, ZOL was generally well tolerated. Conclusions: Treatment with ZOL improves elimination of DTCs. Further studies are needed to determine whether the reduction in DTCs by ZOL provides clinical benefit.