Background Helicopter emergency medical services personnel operating in mountainous terrain are frequently exposed to rapid ascents and provide cardiopulmonary resuscitation (CPR) in the field. The aim of the present trial was to investigate the quality of chest compression only (CCO)‐CPR after acute exposure to altitude under repeatable and standardized conditions. Methods and Results Forty‐eight helicopter emergency medical services personnel were divided into 12 groups of 4 participants; each group was assigned to perform 5 minutes of CCO‐CPR on manikins at 2 of 3 altitudes in a randomized controlled single‐blind crossover design (200, 3000, and 5000 m) in a hypobaric chamber. Physiological parameters were continuously monitored; participants rated their performance and effort on visual analog scales. Generalized estimating equations were performed for variables of CPR quality (depth, rate, recoil, and effective chest compressions) and effects of time, altitude, carryover, altitude sequence, sex, qualification, weight, preacclimatization, and interactions were analyzed. Our trial showed a time‐dependent decrease in chest compression depth ( P =0.036) after 20 minutes at altitude; chest compression depth was below the recommended minimum of 50 mm after 60 to 90 seconds (49 [95% CI, 46–52] mm) of CCO‐CPR. Conclusions This trial showed a time‐dependent decrease in CCO‐CPR quality provided by helicopter emergency medical services personnel during acute exposure to altitude, which was not perceived by the providers. Our findings suggest a reevaluation of the CPR guidelines for providers practicing at altitudes of 3000 m and higher. Mechanical CPR devices could be of help in overcoming CCO‐CPR quality decrease in helicopter emergency medical services missions. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04138446.