This is a prospective study evaluating the safety of single-stage multisegmental thoracolumbar percutaneous balloon vertebroplasty (PVP). To discuss the safety of single-stage multisegmental thoracolumbar PVP. The PVP is a minimally invasive surgery. It is mainly used in the treatment of individuals with serious back pain caused by osteoporotic compression fracture, vertebral metastatic tumors, symptomatic vertebral hemangioma, and multiple myeloma. A total of 50 patients underwent the PVP on 3 or more vertebras compared with 50 cases of PVP on 1 or 2 vertebras. Assessment indexes of safety were: operation time, intraoperative blood pressure change, intraoperative oxyhemoglobin saturation change, intraoperative mental state of patients, postoperative x-ray examination, and results of computed tomography and complications. (1) Average operation time of group A was 125 minutes and that of group B was 56 minutes. (2) Change in arterial pressure of group A was more significant compared with group B, when assessed using the χ test. (3) Pain intensity of group A was compared with group B and a statistical difference was seen only in the patients who underwent PVP on 3 or more vertebras on the first day after surgery. (4) Change in oxyhemoglobin saturation (decreased under 90%) of group A was found to be more significant compared with group B, when assessed using the χ test. (5) No statistical difference in emotional state was found between the 2 groups. (6) There were 4 cases of perivertebral leakage, 1 case of intrapulmonary leakage, and 2 cases of symptoms of intercostal nerve stimulation in group A and 3 cases of perivertebral leakage, 1 case of intrapulmonary leakage, and 1 case of symptoms of intercostal nerve stimulation in group B. High risk exists in single-stage multisegmental thoracolumbar percutaneous vertebroplasty, especially during puncture and bone cement injection, which may cause wide fluctuation of blood pressure and reduce oxygen saturation sharply; however, the surgery is safe to a certain extent, although it requires close intraoperative supervision and shortened operation time.