Using 3D anatomical landmarks from adult human head MRIs, we assessed the magnitude of inter-operator differences in Procrustes-based geometric morphometric analyses. An in depth analysis of both absolute and relative error was performed in a subsample of individuals with replicated digitization by three different operators. The effect of inter-operator differences was also explored in a large sample of more than 900 individuals. Although absolute error was not unusual for MRI measurements, including bone landmarks, shape was particularly affected by differences among operators, with up to more than 30% of sample variation accounted for by this type of error. The magnitude of the bias was such that it dominated the main pattern of bone and total (all landmarks included) shape variation, largely surpassing the effect of sex differences between hundreds of men and women. In contrast, however, we found higher reproducibility in soft-tissue nasal landmarks, despite relatively larger errors in estimates of nasal size. Our study exemplifies the assessment of measurement error using geometric morphometrics on landmarks from MRIs and stresses the importance of relating it to total sample variance within the specific methodological framework being used. In summary, precise landmarks may not necessarily imply negligible errors, especially in shape data; indeed, size and shape may be differentially impacted by measurement error and different types of landmarks may have relatively larger or smaller errors. Importantly, and consistently with other recent studies using geometric morphometrics on digital images (which, however, were not specific to MRI data), this study showed that inter-operator biases can be a major source of error in the analysis of large samples, as those that are becoming increasingly common in the’era of big data’.