The need to enhance the echocardiographic determination of left ventricular ejection fraction is greatest in patients with suboptimal images. Intravenous contrast (CON) and tissue harmonic imaging (THI) are 2 important methods for enhancing endocardial border definition. However, the comparative feasibility and accuracy of THI and contrast-enhanced power harmonic imaging in difficult-to-image patients have not been examined. We assessed the comparative accuracy of THI and CON in determining EF and ventricular volumes in patients with suboptimal fundamental images. We demonstrated that CON is feasible and exhibits a greater correlation with ejection fraction and ventricular volumes determined by radionuclide angiography (standard of comparison) than THI in this difficult-to-image population, with no reported side effects. For both ejection fraction and ventricular volumes, the observer variability was least for CON, intermediate with THI, and greatest for fundamental imaging.