Approximately half or more of patients diagnosed with late malignant tumors may suffer from metastatic bone pain, effective palliation of pain becomes an important part of comprehensive therapy for malignant tumors. In this study, we examined the efficacy and safety of the combined regimen of cryoablation and zoledronic acid in patients of bone metastatic pain. A total of 84 subjects were randomly divided into three groups, and underwent treatments of cryoablation plus zoledronic acid, cryoablation alone, zoledronic acid alone between June 2009 and March 2012. Patients responses had been assessed for a total of 6 months by using the Brief Pain Inventory (BPI)-Short Form. The results showed that the mean response of worst and average pain significantly dropped at week 2 (all P < 0.05) in group with cryoablation treatment but at week 4 (all P < 0.05) in group with zoledronic acid treatment. While between week 16 and week 24, zoledronic acid treatments showed more durable response to worst and average pain compared to cryoablation (all P < 0.05). Cryoablation plus zoledronic acid regimen showed significant drop in worst and average pain between week 1 and week 4 compared to zoledronic acid alone (all P < 0.05) and more durable effect on bone metastatic pain between week 12 and week 24 than cryoablation alone (all P < 0.05). Additionally, no serious adverse effects and complication were observed by this combination use. In conclusion, cryoablation combined with zoledronic acid was safe and effective regimen and showed its superiority of fast response and durable effect on painful bone metastases.