Assessment of the relationship between Pseudoxenodon and Dipsadinae has been hampered by lack of adequate samples. In this paper, we conducted phylogenetic analyses using two mitochondrial genes (12S and 16S rRNA) and one nuclear gene (c-mos) from thirteen specimens representing two species of Pseudoxenodon, together with 84 sequences of caenophidians and an outgroup sequence of Boa constrictor. Our study suggests that the Southeast Asian genus, Pseudoxenodon forms a robust genetic subclade within South American xenodontines, indicating that at least one lineage within this genus entered or returned to the Old World (OW) from the New World (NW) across the Beringian Land Bridge during the early Tertiary and the warm mid-Miocene. It also reveals the high intraspeciifc genomic variation within the populations of Pseudoxenodon macrops, indicating that species diversity of Pseudoxenodon in China is likely underestimated.