To obtain a clear view with angioscopy, blood must be displaced. Carbon dioxide (CO2) gas has proved to be a safe intraarterial contrast agent, and it may have advantages over saline solution as an infusion medium for angioscopy. This study compared the use of CO2 gas and saline solution in the femoral artery, in the presence and absence of a proximal occlusion, in nine pigs and six dogs. The applicability of CO2 gas in the coronary arteries was also evaluated. In total 185 angioscopy procedures were evaluated. With proximal occlusion, angioscopy with CO2 gas was successful in all 28 peripheral procedures, whereas with saline solution only 65% of the procedures resulted in a clear view (p less than 0.005). Without proximal occlusion, angioscopy was successful with CO2 gas and saline solution in 61% and 3% of procedures, respectively (p less than 0.0001). Cardiovascular parameters and blood gases showed minor changes after administration of CO2 gas. During coronary angioscopy with CO2 gas, mechanical heart failure occurred in all instances, which was lethal in 12 animals. None of the animals died as a result of saline angioscopy. In conclusion, CO2 gas is a safe medium for angioscopy in the peripheral arteries and in general offers a better view than saline solution. In contrast to saline solution, without proximal balloon occlusion CO2 gas provided a clear view in 61% of the peripheral procedures. In the coronary arteries, however, CO2 angioscopy was generally fatal in both animal models.