Oecomys tapajinus (Tapajós Oecomys) is currently a junior synonym of Oecomys roberti (Robert's Oecomys), a widely distributed Amazonian mouse, which probably represents a complex of cryptic species. We investigated the taxonomic status of O. tapajinus by integrating phylogenetic analyses of DNA sequences and morphological analyses of museum specimens. We were able to confirm that O. tapajinus is a valid species from eastern Amazonia and the transition to the Brazilian Cerrado, where it is sympatric with O. roberti. Oecomys tapajinus is characterized by a unique combination of morphological traits, high morphological variation, and genetic differentiation and structure related to the complex system of the Amazon River. Potential additional entities within the O. roberti complex emerged from our analyses, and further investigation with larger series may shed light on the taxonomic status of this species complex.