Background: Correct measurement of PO2 and PCO2 is essential to establish appropriate therapy such as long-term oxygen therapy (LTOT) in patients suffering from respiratory failure. Objectives: We aimed to compare common invasive and noninvasive methods for assessing blood gas components for spot check analysis. Methods: Arterial (PaO2, PaCO2) and capillary blood gas (PCBGO2, PCBGCO2) measurements were taken consecutively in a randomized order and were compared with noninvasive measurements obtained from the transcutaneous monitoring of PO2 and PCO2 (PtcO2, PtcCO2, sensor-temperature 44°C). Capillary samples were taken from both arterialized earlobes, where samples of right earlobes were defined as a reference value. Pain assessment of all measurements was evaluated by each subject using the 100-mm visual analogue scale. Results: 83 patients and 17 healthy subjects were included. The mean difference between PaO2 and PtcO2 was 11.9 ± 15.0 mm Hg, with lower limits of agreement (LLA) of -17.4 mm Hg (95% confidence interval (CI) -22.5 to -12.3 mm Hg), and upper limits of agreement (ULA) of 41.1 mm Hg (95% CI 36.0-46.2 mm Hg). The comparison of PaO2 with PCBGO2 showed a mean difference of 5.6 ± 7.2 mm Hg (LLA -11.0; ULA 19.6 mm Hg). The mean difference between PaCO2 and PtcCO2 was 1.1 ± 4.9 mm Hg (LLA -8.6; ULA 10.8 mm Hg) and that between PaCO2 and PCBGCO2 was 0.7 ± 2.0 mm Hg (LLA -3.3; ULA 4.8 mm Hg). The analysis of capillary blood gases (36.2 ± 22.3 mm) was rated as more painful than the analysis of arterial blood gases (26.1 ± 20.6 mm), while transcutaneous measurement was rated as the least painful method (1.9 ± 7.4 mm; all p < 0.0001). Conclusions: The comparison of different methods for blood gas measurements showed substantial differences between capillary and arterial PO2 and between transcutaneous and arterial PO2. Therefore, arterial PO2 analysis is the essential method evaluating indication for LTOT. Nevertheless, comparative analysis further indicated capillary PCO2 as an adequate surrogate for arterial PCO2.