The influence of the nonsteroidal anti-inflammatory drugs indomethacin (10 microgram/ml), mefenamic acid (10 ng/ml) and acetylsalicylic acid (50 microgram/ml) were investigated for their effects on hypoxically perfused rat hearts. Hypoxia-induced mechanical cardiodepression was attenuated to varying degrees by most drugs, although only mefenamic acid reduced the degree of bradycardia. All the agents reduced in some measure the rise in resting tension produced by hypoxic perfusion and enhanced the functional activity of the myocardium upon reoxygenation of hearts made hypoxic for 10 min only. The degree of contracture after reoxygenation was substantially attenuated by all three drugs. Although coronary flow decreased dramatically during prolonged hypoxia, this phenomenon was significantly prevented by the nonsteroidal anti-inflammatory drugs. Cellular Na content of hypoxic hearts treated with mefenamic acid was elevated, whereas no other significant electrolyte changes were observed. The presence of mefenamic acid results in a reduced extracellular space size, whereas cellular water content was increased by both mefenamic acid and acetylsalicylic acid. Calcium transport of isolated mitochondria from hypoxically or normoxically perfused hearts was not modified by any treatment. Indomethacin, acetylsalicylic acid and mefenamic acid all significantly inhibited prostaglandin release from the heart. These results suggest that various nonsteroidal anti-inflammatory drugs may offer some protective influence on hypoxic rat hearts particularly with respect to coronary artery patency during hypoxic perfusion.