This study investigated the accuracy, drift, and clinical usefulness of a new optical transcutaneous oxygen tension (tcPO₂) measuring technique, combined with a conventional electrochemical transcutaneous carbon dioxide (tcPCO₂) measurement and reflectance pulse oximetry in the novel transcutaneous OxiVenT™ Sensor. In vitro gas studies were performed to measure accuracy and drift of tcPO₂ and tcPCO₂. Clinical usefulness for tcPO₂ and tcPCO₂ monitoring was assessed in neonates. In healthy adult volunteers, measured oxygen saturation values (SpO₂) were compared with arterially sampled oxygen saturation values (SaO₂) during controlled hypoxemia. In vitro correlation and agreement with gas mixtures of tcPO₂ (r = 0.999, bias 3.0 mm Hg, limits of agreement − 6.6 to 4.9 mm Hg) and tcPCO₂ (r = 0.999, bias 0.8 mm Hg, limits of agreement − 0.7 to 2.2 mm Hg) were excellent. In vitro drift was negligible for tcPO₂ (0.30 (0.63 SD) mm Hg/24 h) and highly acceptable for tcPCO₂ (− 2.53 (1.04 SD) mm Hg/12 h). Clinical use in neonates showed good usability and feasibility. SpO₂-SaO₂ correlation (r = 0.979) and agreement (bias 0.13%, limits of agreement − 3.95 to 4.21%) in healthy adult volunteers were excellent. The investigated combined tcPO₂, tcPCO₂, and SpO₂ sensor with a new oxygen fluorescence quenching technique is clinically usable and provides good overall accuracy and negligible tcPO₂ drift. Accurate and low-drift tcPO₂ monitoring offers improved measurement validity for long-term monitoring of blood and tissue oxygenation. [Figure not available: see fulltext.].