Analysis of the incisor enamel microstructure of extinct and extant West Indian caviomorph rodents emphasizes a clear microstructural distinction between the Echimyidae (Capromyinae and Heteropsomyinae) among Octodontoidea and the "Heptaxodontidae" whose phylogenetic affinities are debated. All capromyines and heteropsomyines have a pattern of enamel characterized by a rectangular crystallite arrangement, which is biomechanically strongest in limiting crack propagation most efficiently (subtype [Sbt.] 3 of multiserial Hunter-Schreger bands [HSBs]). This enamel condition is exclusive to all mainland octodontoids. In stark contrast, “heptaxodontids” sampled here exhibit much less derived enamel subtypes of multiserial HSBs with parallel to acute angular crystallite arrangement (Sbt. 1 [Clidomys], Sbt. 1–2 [Elasmodontomys], and low acute Sbt. 2 [Amblyrhiza]), less well adapted for prevention of crack propagation. The incisor enamel microstructure of Amblyrhiza and Clidomys is consistent with a chinchilloid assignment, as reflected by the anatomy of their auditory region and their unusual dental pattern. For Elasmodontomys, the primitive condition of its incisor enamel is difficult to reconcile with its highly nested phylogenetic position within the Octodontoidea clade (among the Capromyinae), as recently inferred from aDNA analyses. The different enamel patterns among extinct and extant West Indian caviomorphs indicate distinct high-level taxonomic groups, but restricted to the Octochinchilloi (Octodontoidea and Chinchilloidea) among Caviomorpha. The great diversity of caviomorphs on the Caribbean islands resulted from intra-archipelago diversification through time, but their high-level phylogenetic diversity can only be explained by distinct sources, implying de facto multiple (potentially time-staggered) natural colonizations of the West Indies. The chinchilloid-compatible enamel and dental pattern characterizing Borikenomys from lower Oligocene deposits in Puerto Rico, strongly suggest a link with some of the recently-extinct "heptaxodontids" that would substantiate their much greater antiquity in the Caribbean islands.