Background Recently, bilateral transpedicular kyphoplasty with a single balloon was performed for osteoporotic vertebral body compression fractures (OVCFs) to reduce the fees of the operation, but the time of operation and radiation exposure are longer. The aim of this study was to determine the safety and effectiveness of a single balloon cross-midline expansion via unipedicular approach in kyphoplasty for OVCFs.Methods Thirty-six patients with painful OVCFs (61 vertebrae) were enrolled in this research. Unilateral transpedicular puncture was performed under the fluoroscopy monitoring of an oblique angle down the pedicle. A single balloon was introduced through unipedicular approach. The final balloon position was in the midline of the vertebral body with the balloon cross-midline expansion and bone cement filled. Clinical outcomes were determined by comparison of the preoperative and postoperative visual analogue scale (VAS) and Oswestry disability index (ODI). Radiographic assessment included restoration of vertebral height and correction of kyphosis. Follow-up was conducted for 6-12 months (mean 9.2 months).Results Thirty-six consecutive patients with 61 vertebrae were successfully operated on with a mean operation time of 37.4 minutes per vertebra. All patients had dramatic pain relief and functional recovery within 96 hours after the procedure with no surgery or device-related complications. VAS score improved from 7.27±1.02 preoperatively to 2.71±0.75 postoperatively (P <0.01). ODI score was decreased from (71.14±10.94)% preoperatively to (26.56±6.35)% postoperatively. The average loss of anterior body height was (14.33e2.76) mm before procedure and (10.03±1.83) mm after procedure (P <0.01), while the average loss of middle body height was (10.15e2.70) mm before procedure and (5.89±1.83) mm after procedure (P <0.01). The kyphotic deformity was corrected from (23.43±5.00) degree to (16.16±2.77) degree (P <0.01). The pain relief and functional recovery were substantial and maintained to the last follow-up without any re-collapse or adjacent level fracture.Conclusions A single-balloon cross-midline expansion via unipedicular approach in kyphoplasty for OVCFs is an effective and safe procedure with less cost, less operation time and less radiation exposure when compared with the conventional kyphoplasty technique.