Inner vertebral architecture is poorly known, except in human and laboratory animals. In order to document this topic at a broad comparative level, a 2D-histomorphometric study of vertebral centra was conducted in a sample of 98 therian mammal species, spanning most of the size range and representing the main locomotor adaptations known in therian taxa. Eleven variables relative to the development and geometry of trabecular networks were extracted from CT scan mid-sagittal sections. Phylogeny-informed statistical tests were used to reveal the respective influences of phylogeny, size, and locomotion adaptations on mammalian vertebral structure. The use of random taxon reshuffling and squared change parsimony reveals that 9 of the 11 characteristics (the two exceptions are total sectional area and structural polarization) contain a phylogenetic signal. Linear discriminant analyses suggest that the sampled taxa can be arranged into three categories with respect to locomotion mode: a) terrestrial + flying + digging + amphibious forms, b) coastal oscillatory aquatic taxa, and c) pelagic oscillatory aquatic forms represented by oceanic cetaceans. Pairwise comparison tests and linear regressions show that, when specific size increases, the length of trabecular network (Tt.Tb.Le), as well as trabecular proliferation in total sections (Pr.Tb.Tt), increase with positive allometry. This process occurs in all locomotion categories but is particularly pronounced in pelagic oscillators. Conversely, mean trabecular width has a lesser increase with size in pelagic oscillators. Trabecular orientation is not influenced by size. All tests were corrected for multiple testing. By using six structural variables or indices, locomotion mode can be predicted with a 97.4% success rate for terrestrial forms, 66.7% for coastal oscillatory, and 81.3% for pelagic oscillatory. The possible functional meaning of these results and their potential use for paleobiological inference of locomotion in extinct taxa are discussed. J. Morphol., 2013. © 2013 Wiley Periodicals, Inc.