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Introduction: International Guidelines recommend measurement of end-tidal carbon dioxide (EtCO2) to enhance cardiopulmonary resuscitation (CPR) quality and optimize blood flow during CPR. Numerous factors impact EtCO2 (e.g., ventilation, metabolism, cardiac output), yet few clinical studies have correlated CPR quality and EtCO2 during actual out-of-hospital cardiac arrest (OHCA) resuscitations. The purpose of this study was to describe the association between EtCO2 and CPR quality variables during OHCA. Methods: This is an observational study of prospectively collected CPR quality and capnography data from two EMS agencies participating in a statewide resuscitation quality improvement program. CPR quality and capnography data from adult (≥18 years) cardiac resuscitation attempts (10/2008–06/2013) were collected and analyzed on a minute-by-minute basis using RescueNet™ Code Review. Linear mixed effect models were used to evaluate the association between (log-transformed) EtCO2 level and CPR variables: chest compression (CC) depth, CC rate, CC release velocity (CCRV), ventilation rate. Results: Among the 1217 adult OHCA cases of presumed cardiac etiology, 925 (76.0%) had a monitor-defibrillator file with CPR quality data, of which 296 (32.0%) cases had >1 minute of capnography data during CPR. After capnography quality review, 66 of these cases (22.3%) were excluded due to uninterpretable capnography, resulting in a final study sample of 230 subjects (mean age 68 years; 69.1% male), with a total of 1581 minutes of data. After adjustment for other CPR variables, a 10 mm increase in CC depth was associated with a 4.0% increase in EtCO2 (p < 0.0001), a 10 compression/minute increase in CC rate with a 1.7% increase in EtCO2 (p = 0.02), a 10 mm/second increase in CCRV with a 2.8% increase in EtCO2 (p = 0.03), and a 10 breath/minute increase i