Since the start of Operation Enduring Freedom in 2001, over 42,063 patients have been transported by the United States Air Force aeromedical evacuation system. Critical Care Air Transport Teams (CCATTs) provide care for 5-10% of the injured and ill warriors that are transported on military cargo aircraft to definitive treatment facilities. The purposes of this study were to determine the effect of two stressors of flight, altitude-induced hypoxia and aircraft noise, and to examine the contributions of fatigue and clinical experience on cognitive and physiological performance of CCATT providers. This repeated measures 2 x 2 x 4 factorial study included a sample of 60 military nurses. The participants completed a simulated patient care scenario under aircraft cabin noise and altitude conditions. Cognitive performance was measured with Critical Care Scores, Critical Care Errors and Omissions, and Critical Care Reaction Times during the scenario. Physiological performance was measured four times during the scenario via vital signs and oxygen saturation. Differences in cognitive and physiological performance were analyzed using RM ANOVA. A multiple regression model was developed to determine the independent contribution of fatigue and clinical experience to cognitive and physiological performance as a function of altitude and noise. Critical Care Scores (p = .020) and Errors and Omissions (p = .047) were negatively impacted by aircraft cabin noise. Noise resulted in increase in respiratory rate (p = .019). Critical Care Scores (p < .001) and Errors and Omissions (p = .002) worsened with altitude. Heart rate (p < .001) and respiratory rate (p < .001) increased with altitude, and oxygen saturation (p < .001) decreased. A regression analysis of Critical Care Reaction Time to First Defibrillation with altitude, noise, fatigue, current critical care experience, and experience accounted for 20% of the variance in reaction time (p = .028). The care of critically ill patients is significantly affected by aircraft cabin noise and altitude. Noise and altitude largely act independently of each other. Safety and quality of care may be positively impacted with training and equipment better designed to assist in monitoring and assessment during aeromedical transport.