The percentage flow-mediated dilation index (FMD%) scales the increase in arterial diameter (D diff ) as a constant proportion of baseline artery diameter (D base ). We have demonstrated, albeit with small samples, that the scaling properties of FMD% can lead to biased inferences on endothelial dysfunction. Therefore, we aimed to investigate the underlying rationale and potential bias of FMD% using a selection of new examples from the large (n = 3499) and diverse Multi-Ethnic Study of Atherosclerosis (MESA). In this dataset, we found that smaller values of D diff are associated with larger values of D base , which contradicts the scaling properties of FMD%. Consequently, FMD% 'overscales' and naturally generates an even stronger negative correlation between itself and D base . Using a data simulation, we show that this FMD%-D base correlation can be a statistical artefact due to inappropriate scaling. The new examples we present from MESA indicate that FMD% biases the differences in flow-mediated response between men and women, Framingham risk score categories, and diseased and healthy people. We demonstrate how FMD%, as an exposure for predicting cardiovascular disease, is confounded by its dependency on D base , which itself could be clinically important. This critical review, incorporating an allometric analysis of a large dataset, suggests that the FMD% index has a lessthan-clear rationale, can itself generate the D base -dependency problem, provides biased estimates of differences in the flow-mediated response, complicates the interpretation of the flow-mediated protocol and clouds the causal pathway to vascular disease. These interpretative problems can be resolved by applying accepted allometric principles to the flowmediated response.