The availability of a true 3D dataset provides an opportunity for automation of left ventricular (LV) and left atrial (LA) measurements. Although manual and automated measurements of 3D volumes are known to correlate, the variance is an important parameter for the individual patient. The reasons for discrepancies remain unexplained. We hence aim to explain the disagreement between automated and manual LV and LA volumes.A total of 355 patients underwent standard clinical echo, with offline analysis in both fully- (Heart Model, Philips) and semiautomated (3DQ-Adv, Philips) assessment of routine indices of LV and LA function and shape. Each image was classified according to quality using a 4-point scale as well as the American Society for Echocardiography guidelines for appropriate use of contrast. Bland-Altman plots were used to assess agreement, and t tests were used to assess differences in agreement. Predictors of volume discrepancy were sought with linear regression. Measures of LV and LA volumes were greater with automatic than semiautomatic assessment. The difference in left ventricular end-diastolic volume was dependent on the number of regional wall-motion abnormalities (RWMA) (β = 0.59, P < .04) and image quality (β = 19.71, P = .02). RWMA predicted the difference in left ventricular end-systolic volume (β = 0.83, P < .01) and left atrial end-systolic volume (β = -1.01 P < .01).LV and LA volumes were higher with automatic than semiautomatic assessment. Image quality and RWMA may contribute to this discrepancy. These limitations need to be addressed before fully automatic assessment of 3D echocardiograms can be used in the clinic.