Bone scan index (BSI) has been used to quantify the spread of bone metastasis and be a prognostic indicator in prostate cancer with bone metastases. However, the utility of BSI in breast cancer patients with bone metastasis has not been yet established. We retrospectively reviewed 57 female breast cancer patients with osteoblastic/lytic combined type bone metastases and treated with zoledronic acid after bone metastasis was identified. Serial bone scintigrams were taken at the time of bone metastasis detection and during the 6- and 12-month follow-ups. The scintigrams were analyzed by BONE NAVITM version 1 and the BSI value was calculated. Additionally, serum cancer antigen 15-3 (CA15-3) and carcinoembryonic antigen (CEA) were measured. The patients were divided in 2 distinct groups—group A representing all follow-up BSI values ≤ initial BSI values and group B representing all follow-up BSI values ≥ initial BSI values. The interval changes of CA15-3 and CEA were divided in the same fashion. Kaplan-Meier method and log-rank test revealed that the overall survival rate was significantly greater in group A than those of group B after 6 months (p = 0.011) and 12 months (p = 0.016). Univariate analysis revealed that the overall survival rate was significantly greater in group A than those of group B, after a 6 month period (Hazard Ratio [HR] 5.841; 95% confidence interval [CI] 1.248 – 27.34; p = 0.025) and 12 month period (HR: 4.22; 95% CI 1.17615.15; p = 0.027). Multivariate analysis demonstrated that BSI changes after 6 and 12 months trended toward significance regarding parameters affecting survival rate (age and CA15-3) with a HR = 12.760 (95%CI 1.8110 – 89.850) at 6 months with a p = 0.010 and a HR = 5.0640 (95%CI 1.0590 – 24.220) at 12 months with a p = 0.042. BSI changes after 6 and 12 months appear to be a prognostic factor in breast cancer patients with bone metastasis treated with zoledronic acid.