The traditional bipedicular kyphoplasty was proved to be safe and effective for the treatment of pain associated with osteoporotic vertebral compression fractures (VCFs). Nevertheless, unilateral kyphoplasty would be an attractive alternative to the traditional bipedicular kyphoplasty owing to theoretical speed, safety, and less expense; thus far, the biomechanical testing showed that experimental unilateral kyphoplasty had properties comparable with bipedicular kyphoplasty. To date, no clinical data are available regarding the efficacy and safety of unilateral balloon kyphoplasty. In this prospective observational study, the clinical and radiographic outcomes of the unipedicular (unilateral) balloon kyphoplasty in osteoporotic VCFs are evaluated. Three hundred and seventeen kyphoplasty procedures were performed in 142 patients with osteoporotic VCFs using the unilateral technique. This technique involves the unilateral cannulation of the center of the vertebral body and the placement of a single balloon tamp. To evaluate improvement in pain and physical function, preoperative and postoperative scores of visual analog scale (VAS), SF-36, and Oswestry Disability Index (ODI) were compared at 3 and 12 months postoperatively. Complications related to the procedure and cement extravasation rates were recorded. Height restoration and overall coronal and sagittal spinal alignment were assessed preoperatively and postoperatively. Significant improvement on the VAS, SF-36 scores, and ODI was noted at 3 months postoperatively; these results were preserved at the 12-month follow-up for the 30 patients who completed the SF-36 questionnaire (VAS/ODI scores were available only for 19 of the 30 patients also showing sustained improvement). No complication was recorded; 34 cases (10.73%) of cement extravasation were all asymptomatic. Mean middle height restoration was found 48.9%; when vertebral levels treated were stratified into 2 groups, with or without height restoration (90.1% and 9.9% of all levels, respectively), corrected mean middle height restoration was found 54%. No lateral wedging or changes in the coronal alignment was observed in the unipedicular group. Unipedicular (unilateral) extrapedicular kyphoplasty is both a safe and efficacious alternative to the traditional bipedicular kyphoplasty for the treatment of painful osteoporotic VCFs. As a technique, it is faster, less expensive, and involves less radiation exposure for the surgical suite personnel.