Objectives The objective was to determine the effect of apneic oxygenation (AP OX) on first pass success without hypoxemia (FPS-H) in adult patients undergoing rapid sequence intubation (RSI) in the emergency department (ED). Methods Continuous quality improvement data were prospectively collected on all patients intubated in an academic ED from July 1, 2013, to June 30, 2015. During this period the use of AP OX was introduced and encouraged for all patients undergoing RSI in the ED. Following each intubation, the operator completed a standardized data form that included information on patient, operator, and intubation characteristics. Adult patients 18 years of age or greater who underwent RSI in the ED by emergency medicine residents were included in the analysis. The primary outcome was FPS-H, which was defined as successful tracheal intubation on a single laryngoscope insertion without oxygen saturation falling below 90%. A multivariate logistic regression analysis was performed to determine the effect of AP OX on FPS-H. Results During the 2-year study period, 635 patients met inclusion criteria. Of these, 380 (59.8%) had AP OX utilized and 255 (40.2%) had no AP OX utilized. In the AP OX cohort the FPS-H was 312/380 (82.1%) and in the no AP OX cohort the FPS-H was 176/255 (69.0%) (difference = 13.1%, 95% confidence interval [CI] = 6.2% to 19.9%). In the multivariate logistic regression analysis, the use of AP OX was associated with an increased odds of FPS-H (adjusted odds ratio = 2.2, 95% CI = 1.5 to 3.3). Conclusions The use of AP OX during the RSI of adult patients in the ED was associated with a significant increase in FPS-H. These results suggest that the use of AP OX has the potential to increase the safety of RSI in the ED by reducing the number of intubation attempts and the incidence of hypoxemia.