The effects of carbon monoxide (CO) or nitrogen (N₂) anoxia were assessed and compared in stimulated (360 beats/min) and unstimulated isolated rat hearts. The hearts were perfused through the aorta with Krebs-Henseleit solution aerated with 95% O₂5% CO₂ (O₂). Heart rate, pulse pressure, perfusate flow, and perfusate lactate concentrations were recorded. After 30 min of O₂ perfusion, the hearts were challenged with 95% CO5% CO₂ (CO) or 95% N₂5% CO₂ (N₂) for 10 min. The preparations were then reoxygenated and allowed to recover for 10 min. In the unstimulated hearts, CO depressed heart rate, pulse pressure, and perfusate flow earlier than did N₂. Lactate concentrations increased to a greater extent with N₂ than with CO. With reoxygenation heart rate, pulse pressure, and lactate concentrations returned to control values earlier in the CO hearts. The differences observed in pulse pressure and lactate concentrations with CO and N₂ anoxia disappeared with stimulation. There were no significant differences in water or glycogen contents after CO or N₂ in either the unstimulated or stimulated preparations. These results suggest that CO may have a direct effect on the myocardium in addition to its well-known anoxic effect.