A large animal with diminished cardiac function would be desirable for chronic testing of pathophysiologic responses to many human-sized devices and other therapies, especially if this model did not require prior surgical interventions or extensive technical skill and expense. Overdoses of monensin, widely used in the cattle industry as a growth promotant, are cardiotoxic, suggesting its possible use in creating cardiomyopathy. We gave a single oral dose of monensin (20 to 40 mg/kg) to 13 calves (55 to 90 kg) to produce diminished cardiac function. Hemodynamics and cardiac geometry were monitored for as long as 21 days postinduction. Within 3 days, there were signs of decreased cardiac function, as evidenced by a 10- to 20-mm Hg decrease in peak systolic blood pressure (P < 0.01 versus baseline) and a 2- to 9-mm Hg increase in central venous pressure (P < 0.01 versus baseline). There was a trend towards an increase in left ventricular end-systolic lumen diameter. Compared with those of similar-sized normal animals, stroke volume was 42% lower (P < 0.05), left atrial pressure was 67% higher (P < 0.01), and end-diastolic left ventricular pressure was 143% higher (P < 0.05). Histopathologic analysis showed extensive cardiomyocyte death. These results suggest that monensin could provide a simple, noninvasive, inexpensive, and likely irreversible means of producing clinically relevant diminished cardiac function in a human-sized animal model.