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Simple Summary: We report the first clinical use of Endosight, a new guidance system for percutaneous interventional procedures based on augmented reality, to guide percutaneous thermal ablations. The new system was demonstrated to be precise and reliable, with a targeting accuracy of 3.4 mm. Clinically acceptable, rapid setup and procedural times can be achieved. Background: Over the last two decades, augmented reality (AR) has been used as a visualization tool in many medical fields in order to increase precision, limit the radiation dose, and decrease the variability among operators. Here, we report the first in vivo study of a novel AR system for the guidance of percutaneous interventional oncology procedures. Methods: Eight patients with 15 liver tumors (0.7–3.0 cm, mean 1.56 + 0.55) underwent percutaneous thermal ablations using AR guidance (i.e., the Endosight system). Prior to the intervention, the patients were evaluated with US and CT. The targeted nodules were segmented and three-dimensionally (3D) reconstructed from CT images, and the probe trajectory to the target was defined. The procedures were guided solely by AR, with the position of the probe tip was subsequently confirmed by conventional imaging. The primary endpoints were the targeting accuracy, the system setup time, and targeting time (i.e., from the target visualization to the correct needle insertion). The technical success was also evaluated and validated by co-registration software. Upon completion, the operators were assessed for cybersickness or other symptoms related to the use of AR. Results: Rapid system setup and procedural targeting times were noted (mean 14.3 min; 12.0–17.2 min; 4.3 min, 3.2–5.7 min, mean, respectively). The high targeting accuracy (3.4 mm; 2.6–4.2 mm, mean) was accompanied by technical success in all 15 lesions (i.e., the complete ablation of the tumor and 13/15 lesions with a >90% 5-mm periablational margin). No intra/periprocedural complications or operator cybersickness were observed. Conclusions: AR guidance is highly accurate, and allows for the confident performance of percutaneous thermal ablations. [ABSTRACT FROM AUTHOR]