Objective: To compare transcutaneous CO 2 (TCCO 2) and end-tidal CO 2 (ETCO 2) monitoring during one-lung ventilation (OLV). Design: Prospective study. Setting: Operating room of a University Hospital. Participants: Fifteen patients undergoing thoracic surgical procedures in whom one-lung ventilation was deemed necessary. Intervention: TC and ETCO 2 monitors were used simultaneously in the patients and compared with arterial blood gases (ABGs) during 2-lung ventilation and OLV. Measurements and Main Results: During 2-lung ventilation (TLV), the ET to PaCO 2 difference was 3.9 ± 1.6 mmHg, whereas the TC to PaCO 2 difference was 2.5 ± 0.8 mmHg ( p = 0.0049). During OLV, the ET to PaCO 2 difference increased to 5.8 ± 2.3 mmHg, whereas the TC to PaCO 2 difference was 2.7 ± 1.4 mmHg ( p = 0.0049 for ET to PaCO 2 difference during OLV v TLV and p = 0.0004 for ET to PaCO 2 gradient v TC to PaCO 2 gradient during OLV). During TLV, the difference between the ET and PaCO 2 was ≤5 mmHg in 13 of 15 patients, whereas the difference between the TC and PaCO 2 was ≤5 mmHg in 15 of 15 patients ( p = not significant). During OLV, the difference between the ET and the PaCO 2 was ≤5 mmHg in 6 of 15 patients, whereas the difference between the TC and PaCO 2 was ≤5 mmHg in 14 of 15 patients ( p = 0.0052, odds ratio 21.0 for ET v TC techniques and p = 0.02, odds ratio 9.75 for ET to PaCO 2 during TLV v OLV). Conclusions: During OLV, TCCO 2 monitoring provides a more accurate estimate of PaCO 2 than ET techniques.