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Endothelial and epithelial cells are commonly used for assessing blood–brain barrier (BBB) permeability of the drug candidates. However, the additional value provided by the endothelial cells as an in vitro BBB drug permeability model is not clear. The aim of the study was to identify the molecular descriptors that impact on drug permeability through the primary bovine brain microvessel endothelial cell model (BBMEC) and compare descriptors with those determined for epithelial cell models. In addition, we intended to clarify the reasons for previously reported similar in vitro–in vivo correlations between endothelial and epithelial cell models and to evaluate whether BBMEC can provide additional value. The permeability of model drugs through the BBMEC was determined. Principal component analysis (PCA) model was created with twenty-two model drugs and this model was used to interpret the molecular descriptors. The present study demonstrates that hydrophobic interactions, the balance between the hydrophilic and lipophilic moieties in the drug, hydrophilic interactions and hydrogen bonding interactions are the key descriptors depicting drug permeability through the BBMEC. There were no clear differences between the molecular descriptors determining the in vitro permeability of drugs in the endothelial and epithelial cells. In conclusion, the predominance of passive permeability in in vitro setups may explain the similar in vitro–in vivo correlations previously obtained between endothelial and epithelial cell models. Therefore, the present results further support previous findings that epithelial cell models can be used instead of laborious primary endothelial cells as an in vitro BBB permeability model when passive transport is mainly being evaluated.