Study Objective: To compare the concentration of a rescuer's exhaled O 2 and CO 2 during mouth-to-mouth ventilation with or without chest compression. Design: Prospective repeated measures study. Simulated one- and two-rescuer cardiopulmonary resuscitation (CPR) was performed as recommended by the American Heart Association. Setting: University laboratory. Participants: Fifty-five healthcare professionals certified in basic and advanced cardiac life support volunteered as rescuers in this study. Measurements and results: Thirty-three volunteers performed one-rescuer CPR, and 22 volunteers performed two-rescuer CPR. Minute ventilation for both groups increased 50% to 130% during CPR (p < 0.05). During the performance of CPR, the concentration of exhaled O 2 increased from 16.4 ± 0.7% to 16.9 ± 0.5% in the one-rescuer CPR group and from 16.5 ± 0.9% to 17.8 ± 0.6% in the two-rescuer CPR group (p < 0.05). The concentration of exhaled CO 2 in the one-rescuer CPR group did not change significantly throughout the entire experiment, but decreased in the two-rescuer CPR group from a baseline measurement of 4.0 ± 0.6% to 3.5 ± 0.4% (p < 0.05). During CPR, the concentration of exhaled CO 2 was 4.0 ± 0.4% in the one-rescuer CPR group compared with 3.5 ± 0.4% in the two-rescuer CPR group (p < 0.05). Conclusions: The gas given by mouth-to-mouth ventilation is a hypercarbic and hypoxic mixture compared with room air. Mouth-to-mouth ventilation is the only circumstance in which a hypercarbic and hypoxic gas is given as therapy. Further laboratory and clinical studies are necessary to determine the effect of mouth-to-mouth ventilation during CPR.