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Objectives: A validated means to predict inhospital cardiac arrest is lacking. The purpose of this study was to evaluate the changes in end-tidal carbon dioxide, as it correlates with the progression to inhospital cardiac arrest in ICU patients. Design, Setting, and Patients: Single-center, retrospective cohort study of mechanically ventilated ICU patients (age > 18 yr old) having inhospital cardiac arrest with advanced cardiac life support and continuous end-tidal carbon dioxide monitoring at a single academic center from 2014 to 2017. Demographics, clinical variables, and outcomes were collected. End-tidal carbon dioxide was collected from 5 to 2,880 minutes before inhospital cardiac arrest. Data were analyzed using descriptive statistics, and model estimates were generated using a repeated-measures categorical model with restricted maximum likelihood estimation and fully specified (autoregressive) covariance to assess the effect of time on changes in end-tidal carbon dioxide. Measurements and Main Results: A total of 788 patients were identified and 104 met inclusion criteria, where 62% were male with an average age of 58.5 years. Seventy-four percent required vasopressors and 72% experienced pulseless electrical activity. Mean end-tidal carbon dioxide 5 minutes prior to inhospital cardiac arrest was significantly lower than all evaluated time points except 180 minutes (p < 0.05). One patient survived to hospital discharge. In multivariate logistic regression modeling for return of spontaneous circulation, a greater change in the prearrest end-tidal carbon dioxide maximum to prearrest end-tidal carbon dioxide minimum was associated with a decreased likelihood of return of spontaneous circulation (odds ratio 0.903; 95% CI, 0.832–0.979; p = 0.014). Additionally, a change from prearrest end-tidal carbon dioxide maximum to prearrest end-tidal carbon dioxide minimum greater than 17 mm Hg was associated with a decreased likelihood of return of spontaneous circulation and odds ratio 0.150; 95% CI, 0.036–0.66; p = 0.012). Conclusions: Mean end-tidal carbon dioxide is significantly lower immediately before inhospital cardiac arrest. The statistical and clinical significance of end-tidal carbon dioxide may highlight its utility for predicting inhospital cardiac arrest in ICU patients. Comparison analysis and modeling explorations in a larger cohort are needed.