Chronic obstructive pulmonary disease (COPD) patients in hypercapnic respiratory failure require multiple arterial blood gas (ABG) analysis for monitoring. It is a painful, invasive, and expensive investigation. This study was aimed at finding an agreement between end-tidal carbon dioxide (ETCO, a noninvasive modality) and arterial carbon dioxide (PaCO) in COPD patients with acute exacerbation on mechanical ventilation. A prospective observational study was conducted in COPD patients who required mechanical ventilation. ETCO was recorded by mainstream capnography along with ABG analysis. An agreement between PaCO and ETCO was assessed. The effect of various factors on correlation was also studied. A total of 100 patients with COPD in hypercapnic respiratory failure were included. Seventy-three percentage of patients were managed on invasive mechanical ventilation (IMV). The mean ETCO and PaCO were 48.66 ± 15.57 mm Hg and 75.52 ± 21.9 mm Hg, respectively. There was a significant correlation between PaCO and ETCO values ( = 0.82, 95% confidence interval of = 0.78-0.86, <0.0001). The Bland-Altman analysis shows the mean bias as -19.4 (95% limits of agreement = -40.0-1.1). Pearson's correlation coefficient was 0.84 in intubated patients and 0.58 in patients on noninvasive ventilation (NIV). Pearson's correlation coefficient between PaCO and ETCO in subjects with consolidation, cardiomegaly, hypotension, and raised pulmonary artery pressures was 0.78, 0.86, 0.85, and 0.86, respectively. Mainstream ETCO measurement accurately predicts the PaCO in COPD patients on IMV. However, for patients on NIV, ETCO is insufficient in monitoring PaCO levels due to weak correlation. ETCO can be used as a noninvasive modality in intensive care unit for monitoring the PaCO in COPD patients on IMV. This can reduce the requirement of arterial blood sampling to a minimum number, in turn, reducing the cost of the treatment and discomfort to the patients. Tyagi D, Govindagoudar MB, Jakka S, Chandra S, Chaudhry D. Correlation of PaCO and ETCO in COPD Patients with Exacerbation on Mechanical Ventilation. Indian J Crit Care Med 2021;25(3):305-309.