To fully utilize the potential of newly developed mouse models with specific genetic mutations, it is necessary to study the functional consequences of genetic manipulation in the fully intact animal. To this end, the purpose of the present study was to develop and validate a methodology for the study of myocardial performance in the fully intact, closed-chest mouse. Left ventricular function was evaluated in euthyroid, hypothyroid, and hyperthyroid mice, animals with well-documented alterations in myocardial function. The mice were anesthetized and instrumented with polyethylene catheters in the right femoral artery and vein and with a Millar MIKRO-TIP transducer in the left ventricle via the right carotid artery. Structural and functional evidence suggested that the instrumentation procedure did not cause myocardial damage, valvular insufficiency, or aortic obstruction. Isovolumic indexes of myocardial contractility derived from the left ventricular pressure pulse and its first derivative demonstrated a 40% increase in contractility in the hyperthyroid animals and a 40% decrease in contractility in the hypothyroid animals. Similar differences in the indexes of relaxation were observed. Furthermore, isoproterenol dose-response relationships of these contractile parameters were blunted in the hypothyroid animals and augmented in the hyperthyroid animals compared with euthyroid control animals. Given the small size of the mouse and the high frequency of the cardiac cycle, these data demonstrate the feasibilty of combining a high-fidelity, microtip manometer with a high-speed data-acquisition system to obtain faithful recordings of cardiac performance in the fully intact mouse.