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Background: The objective of this retrospective study was to analyze the morphological changes of the upper arch after two protocols of expansion, the Invisalign® First system and rapid maxillary expansion (RME), in mixed dentition by means of geometric morphometric analysis (GMM). Methods: Digital dental casts of 32 children treated either with RME (RME group: 17 subjects; mean age 8.1 years) or the First system (First group: subjects; mean age 8.4 years) were collected. For both the RG and FG, pre-(T1) and post-treatment(T2) digital models were created. A total of 14 landmarks were digitized and GMM was applied. Procrustes analysis and principal component analysis (PCA) were performed. Results: The PC1 resulting from the T2–T1 comparison in the RG g showed statistically significant morphological changes in the posterior region of the upper arch shape, without significant variations in the anterior region. The comparison of the T2–T1 changes in the FG showed an increase in the transverse dimension at the level of the canine and the first deciduous molar widths, with morphological variation in the anterior region due to frontal teeth alignment. Conclusions: The First system induced shape modifications of the upper arch during expansion in contrast to RME. The FG presented an improvement in the maxillary arch shape, while the RG maintained the initial triangular shape.