Objectives: Low tidal volume ventilation (LTVV) is a ventilatory strategy with the advantages of minimizing diaphragm movements and reducing hypercapnia and barotrauma risks. This preliminary study aims to report on the safety and effectiveness of LTVV applied during percutaneous US-guided liver ablations of focal malignancies. Methods: Patients affected by focal liver malignancies treated with percutaneous microwaves ablation were retrospectively included in this single-center analysis. Arterial gas analysis was performed immediately before and after ablation to evaluate the arterial pH, partial pressure of carbon dioxide (pCO₂), partial pressure of oxygen (pO₂), and plasma lactate levels. The primary endpoint of this study was to evaluate the safety and efficacy of LTVV during percutaneous liver cancer ablation. The secondary endpoint was to assess the procedural technical success in terms of correct needle probe targeting without the need for repositioning. Results: Ten patients affected by a single liver lesion had been analyzed. The ASA score was three in all patients, with three patients also suffering from COPD. The procedural technical success was 100%: ablations were performed with a single liver puncture without the need for changing access or repositioning the needle. No variations in post-ablation arterial gas analysis requiring anesthesiological management remodulation occurred. Lactate levels remained stable and hemodynamic balance was preserved during all procedures. No switch to standard volume ventilation was required. Conclusions: In this preliminary study, LTVV was a safe and effective anesthesiological protocol in patients treated with percutaneous ablations of liver malignancies, offering an ideal balance between patient safety and percutaneous needle probe positioning precision. Larger prospective studies are needed to confirm these findings.