Objective: To evaluate the effect of zoledronic acid combined with radiotherapy on the breast cancer patients with skeletal metastases. Methods: Seventy-six breast cancer patients with skeletal metastases were randomly allocated into a zoledronic acid combined radiotherapy group (n=26), a radiotherapy group (control group, n=25) alone, and a zoledronic acid group (control group, n=25) alone. The therapeutic effect was observed in each group. Results: Treatment with zoledronic acid combined with radiotherapy at the end of treatment was superior to zoledronic acid alone in the treatment of bone pain, Verbal Rating Scale (VRS) score was statistically significant (P<0.05), but there was no significant difference in pain relief between the combination therapy group and the radiotherapy group alone, VRS score was not statistically significant (P>0.05); after 2 months of treatment, the pain relief of combination therapy group was better than the zoledronic acid group and radiotherapy group alone, VRS score was statistically significant (P<0.05). Compared with the zoledronic acid group and radiotherapy group alone, the combination therapy group can significantly improve patient activity and quality of life (P<0.05). Conclusion: Zoledronic acid combined with radiotherapy for the breast cancer patients with skeletal metastases has a significant effect, which can control bone pain strongly and significantly improve patient activity and quality of life. It’s effect is better than radiotherapy group or zoledronic acid group alone. This treatment is ideal for breast cancer with skeletal metastases.