BACKGROUND: The ratio of end-tidal CO2 pressure to arterial partial pressure of CO2 (P ETCO2 /P aCO2 ) was recently suggested for monitoring pulmonary gas exchange in patients with ARDS associated with COVID-19, yet no evidence was offered supporting that claim. Therefore, we evaluated whether P ETCO2 /P aCO2 might be relevant in assessing ARDS not associated with COVID-19. METHODS: We evaluated the correspondence between P ETCO2 /P aCO2 and the ratio of dead space to tidal volume (VD/VT) measured in 561 subjects with ARDS from a previous study in whom P ETCO2 data were also available. Subjects also were analyzed according to 4 ranges of P ETCO2 /P aCO2 representing increasing illness severity (>/= 0.80, 0.6-0.79, 0.50-0.59, and < 0.50). Correlation was assessed by either Pearson or Spearman tests, grouped comparisons were assessed using either ANOVA or Kruskal-Wallis tests and dichotomous variables assessed by Fisher Exact tests. Normally distributed data are presented as mean and standard deviation(SD) and non-normal data are presented as median and inter-quartile range (IQR). Overall mortality risk was assessed with multivariate logistic regression. Alpha was set at 0.05. RESULTS: P ETCO2 /P aCO2 correlated strongly with VD/VT (r = -0.87 [95% CI -0.89 to -0.85], P < .001). Decreasing P ETCO2 /P aCO2 was associated with increased VD/VT and hospital mortality between all groups. In the univariate analysis, for every 0.01 decrease in P ETCO2 /P aCO2 , mortality risk increased by approximately 1% (odds ratio 0.009, 95% CI 0.003-0.029, P < .001) and maintained a strong independent association with mortality risk when adjusted for other variables (odds ratio 0.19, 95% CI 0.04-0.91, P = .039). P ETCO2 /P aCO2 < 0.50 was characterized by very high mean +/- SD value for VD/VT (0.82 +/- 0.05, P < .001) and high hospital mortality (70%). CONCLUSIONS: Using P ETCO2 /P aCO2 as a surrogate for VD/VT may be a useful and practical measurement for both management and ongoing research into the nature of ARDS.