We evaluated the effects of Escherichia coli endotoxin on the peripheral vascular hemodynamics and myocardial function of the newborn lamb to understand how gram-negative endotoxemia can lead to cardiovascular collapse in newborn infants. Fifteen lambs, 0–3 d old, were acutely instrumented with a micromanometer-tipped catheter and two pairs of ultrasonic crystals to measure left ventricular (LV) pressure and LV anterior-posterior and septal-free wall dimensions, a fluid-filled catheter for monitoring aortic pressure, and an electromagnetic flow probe to measure systemic blood flow. Cardiovascular performance was evaluated by measuring or deriving the following variables: mean arterial blood pressure (MABP), LV pressure, heart rate, stroke volume, systemic vascular resistance, LV dp/dt, end-diastolic area, arterial elastance, and end-systolic elastance (the slope of the end-systolic pressure-area relationship) as an index of contractility independent of loading conditions and heart rate. Once instrumented, nine lambs received endotoxin, 0.5 mg/kg i.v., and six animals, serving as controls, received a saline infusion. Of the endotoxin-treated lambs, five survived the duration of the study (120 min from the beginning of the endotoxin infusion), and four died by 90 min from the beginning of the endotoxin infusion. No significant changes in any of the cardiovascular variables occurred in the control group. A significant decrease in MABP was seen in all endotoxin-treated animals by 45 min after the beginning of the endotoxin infusion. MABP decreased by 52% from baseline in the survivors and 38% in the nonsurvivors. In the survivors, the MABP stabilized with saline boluses, whereas in the nonsurvivors MABP continued to decrease until death. In the survivors, end-systolic elastance remained stable, and, despite changes in afterload, LV dp/dt also remained stable throughout the study. In the nonsurvivors, the end-systolic elastance and LV dp/dt exhibited a progressive decline until death, with the changes in the end-systolic elastance preceding the changes in LV dp/dt. End-diastolic area and stroke volume remained stable during the study in both groups of endotoxin-treated animals, decreasing in the nonsurvivors just before death. Because the changes in end-systolic elastance and LV dp/dt clearly preceded the decreases in end-diastolic area and stroke volume in the nonsurvivors, we conclude that the myocardial depression in the nonsurvivors was primarily due to depressed myocardial contractility, not decreased preload.