With the ageing of the global population, the incidence of osteoporotic vertebral compression fractures (OVCFs) is increasing. To assess the safety and efficacy of O-arm- and guide-device-assisted personalized percutaneous kyphoplasty (PKP) for treating thoracolumbar OVCFs, a total of 38 consecutive thoracolumbar OVCF patients who underwent bilateral PKP assisted with an O-arm and a guide device (O-GD group, n = 16) or traditional fluoroscopy (TF group, n = 22) from January 2020 to December 2021 were retrospectively reviewed, and their epidemiologic, clinical and radiological outcomes were analysed. The operation time was significantly decreased (p < 0.001) in the O-GD group (38.3 ± 12.2 min) compared with the TF group (57.2 ± 9.7 min). The number of intraoperative fluoroscopy exposures was significantly decreased (p < 0.001) in the O-GD group (31.9 ± 4.5) compared with the TF group (46.7 ± 7.2). Intraoperative blood loss was significantly decreased (p = 0.031) in the O-GD group (6.9 ± 2.5 mL) compared with the TF group (9.1 ± 3.3 mL). No significant difference (p = 0.854) in the volume of injected cement was observed between the O-GD group (6.8 ± 1.3 mL) and the TF group (6.7 ± 1.7 mL). Both the clinical and radiological outcomes, including the visual analogue scale score for pain, Oswestry Disability Index and anterior height and local kyphotic angle of the fractured vertebrae, were significantly improved at the postoperative and final follow-up but did not differ between the two groups. The incidence of cement leakage and refracture of the vertebral body was similar in the two groups (p = 0.272; p = 0.871). Our preliminary study demonstrated that O-GD-assisted PKP is a safe and effective procedure that presents a significantly shorter operation time, fewer intraoperative fluoroscopy exposures and less intraoperative blood loss than the TF technique.