Indomethacin, meclofenamic acid and acetylsalicylic acid are prostaglandin synthetase-inhibiting, nonsteroidal anti-inflammatory drugs. Their effects on hemodynamic and enzymatic responses to coronary artery occlusion were evaluated in the cat. The direct effects of these drugs on isolated tissue preparations (i.e., cat papillary muscle, aortic strip and liver lysosomes) were also studied. None of the drugs tested exhibited any significant hemodynamic or biochemical effects which would indicate protection against damage due to myocardial ischemia during the 5-hour experimental period. Furthermore, only indomethacin produced significant effects on the isolated tissues studied. Indomethacin increased the tension of aortic strips confirming a pressor effect seen in the intact animal and exerted a modest stabilization of isolated liver lysosomes. All three anti-inflammatory drugs inhibited prostaglandin F2alpha, release in heart homogenates by 82 to 87%. It is concluded that nonsteroidal anti-inflammatory drugs do not significantly influence the early course of myocardial ischemia in the cat, in contrast to the previously reported preservation of myocardial integrity afforded by dexamethasone and methylprednisolone.