Summary Many previous studies have reported excellent clinical results with percutaneous kyphoplasty (PKP). In contrast, numerous complications and problems have also been reported, such as puncture difficulty, cement leakage, and adjacent vertebral fracture. Introduction This study is to evaluate the application and clinical outcomes of unilateral transverse process-pedicle and bilateral PKP in the treatment of osteoporotic vertebral compression fractures (OVCF). Methods A total of 56 cases with two levels thoracolumbar OVCF were randomly assigned for treatment with unilateral transverse process-pedicle and bilateral PKP. The patients were followed up postoperatively and were assessed mainly with regard to clinical and radiologic outcomes. Clinical outcomes were evaluated with mainly the use of a visual analogue scale (VAS) for pain. Radiologic outcomes were assessed mainly on the basis of radiation dose and bone cement distribution. Results The operation was completed successfully in 56 cases. In the unilateral level, the operation time, the volume of the injected cement, and radiation dose were significantly less than bilateral level. All patients had significantly improvement on VAS score after the procedures, compared with their preoperative period. In the bilateral level, 7 patients had obvious pain in the puncture sites at 1 month postoperatively caused by facet joint violation. With local block treatment, the pain disappeared in all patients at the last follow-up. Conclusion Both bilateral and unilateral PKP are relatively safe and effective treatments for patients with painful OVCF. But unilateral PKP received less radiation dose and operation time, offered a higher degree of deformity correction, and resulted in less complication than bilateral.