Background and Objectives: Navigated pedicle screw placement is becoming increasingly popular, as it has been shown to reduce the rate of screw misplacement. We present our intraoperative workflow and initial experience in terms of safety, efficiency, and clinical feasibility with a novel system for a 3D C-arm cone beam computed-tomography-based navigation of thoracolumbar pedicle screws. Materials and Methods: The first 20 consecutive cases of C-arm cone beam computed-tomography-based percutaneous pedicle screw placement using a novel navigation system were included in this study. Procedural data including screw placement time and patient radiation dose were prospectively collected. Final pedicle screw accuracy was assessed using the Gertzbein-Robbins grading system. Results: In total, 156 screws were placed. The screw accuracy was 94.9%. All the pedicle breaches occurred on the lateral pedicle wall, and none caused clinical complications. On average, a time of 2:42 min was required to place a screw. The mean intraoperative patient radiation exposure was 7.46 mSv. Conclusions: In summary, the investigated combination of C-arm CBCT-based navigation proved to be easy to implement and highly reliable. It facilitates the accurate and efficient percutaneous placement of pedicle screws in the thoracolumbar spine. The careful use of intraoperative imaging maintains the intraoperative radiation exposure to the patient at a moderate level.