Background Accurate, reproducible, noninvasive determination of left ventricular (LV) volumes and election fraction (EF) is important for clinical assessment, risk stratification, selection of therapy, and serial monitoring of patients with cardiovascular disease. Three-dimensional echocardiography (3DE) approaches have demonstrated significantly greater accuracy than current clinical 2DE, but the clinical utility of 3DE has been limited because of the need for substantial modifications to scanning technique (eg, all image acquisition from a single acoustic window) or cumbersome additional hardware. We describe a novel 3DE system without these limitations and its application to patients. Methods and Results Twenty-five patients were examined by 3DE, 2DE, and magnetic resonance imaging (MRI). The 3DE system used a magnetic scanhead tracking device, and volumes were computed with a novel deformable shell model. End-diastolic volumes and EF by MRI ranged from 96 to 375 mt and 18% to 73%, respectively. There was excellent correlation, without statistically significant differences, between MRI and 3DE for end-systolic volume (ESV) (r(2) = 0.99) and end-diastolic volume (EDV) (r(2) = 0.98), ventricular stroke volume (SV) (r(2) = 0.93), and EF (r(2) = 0.97), with standard error estimates less than 10 mi for volumes and 3% for EF. Conventional 2DE consistently underestimated volumes (EDV, P < .01; ESV, P < .01; SV, P < .05); correlations with MRI were r2 = 0.91 for ESV, r(2) = 0.88 for EDV, r(2) = 0.62 for SV, and r(2) = 0.72 For EF. Standard error estimates ranged from 16 to 20 mi for ventricular volumes and 9% for EF. Interobserver variability was reduced S-fold with use of 3DE. Conclusions The novel 3DE system allows unrestricted selection and combination of acoustic windows in a single examination, improves accuracy of estimates of LV volumes and EF 3-fold compared with 2DE, and is practical for routine clinical assessment of LV size and Function in patients with a wide range of cardiac pathology.