Background: Zoledronic acid (ZA) reduces the onset risk of skeletal-related events (SRE) caused by bone metastasis in prostate cancer (PCa) patients and improves the QOL. Therefore ZA has become a standard supportive therapy for PCa with bone metastasis. However, it remains unclear when the physicians should start ZA treatment. In the present study, we investigated whether combination of ZA could delay PSA relapse of PCa and prevent SREs. Methods: The patients were randomly classified in two groups (combined androgen blockade (CAB) alone group and CAB + ZA treatment group). In the CAB + ZA group, 4 mg ZA was intravenously administered every 4 weeks with the start of treatment. The first end point was a period to PSA relapse, and the secondary end point was SREs rate. Results: Untreated 60 PCa patients with bone metastasis were enrolled by 2011 from 2006. Thirty one patients were treated with CAB alone and 29 patients were treated with CAB + ZA. There were no significant differences in the baseline characteristics in the both groups, and the mean observation period was 27.4 months and 32.1 months, respectively. Although there was no significant difference in progression free survival (PFS) (p=0.073), tendency that CAB + ZA shows better PFS than CAB alone group was observed (time to 50% PFS was extended 11.6 months than CAB alone group). Moreover, the sub analysis using the patients with more than Gleason score 7, CAB +ZA group showed significantly longer PFS than the CAB group (p=0.021). And statistically significant difference was recognized in SRE rate between the two groups (p=0.019), ZA tended to delay the occurrence of SRE in PCa patients. Conclusions: This result indicates that the use of ZA at the beginning of hormonal therapy have not only a preventive effect on the occurrence of SREs but also a relapse-delaying effect, especially in the patients with high Gleason score and severe bone metastasis. Though careful observation is essential, since the long-term use of ZA may increase the incidence of adverse effects, CAB-ZA treatment may be recommended for the treatment of PCa patients with bone metastasis.