Our goals were to: (1) develop a technique for 3-dimensional (3D) direct, model-independent quantitative assessment of left ventricular (LV) volume and ejection fraction based on semiautomated detection of LV endocardial surface from transthoracic near real-time full matrix-array 3D echocardiographic (FM3DE) imaging; (2) evaluate the accuracy of LV volumes obtained with this technique, using cardiac magnetic resonance imaging (MRI) measurements as the reference for comparison; and (3) determine the effects of contrast enhancement on the accuracy of FM3DE measurements. A total of 46 patients underwent 2-dimensional echocardiography, FM3DE, and cardiac MRI. End-diastolic volume, end-systolic volume, and ejection fraction were derived from endocardial borders manually traced from 2-dimensional echocardiographic images and from semiautomatically detected LV cavity from FM3DE data. In 14 patients, FM3DE was also acquired with contrast. All measurements were compared with MRI values using linear regression and Bland-Altman analyses. FM3DE was feasible in 44 of 46 patients with LV volumes < 345 mL. LV volumes and ejection fraction computed from FM3DE resulted in higher levels of agreement with MRI than conventional 2-dimensional echocardiography, with lower interobserver variability. With contrast enhancement, FM3DE significantly underestimated LV volumes and showed increased interobserver variability. Semiautomated LV endocardial surface detection from FM3DE images is feasible and results in fast and accurate assessment of LV function.