The basic helix-loop-helix/Per-Arnt-Sim (bHLH-PAS) homology protein family is an important class of transcriptional regulators that are involved in a wide variety of biological processes. In a previous study, we characterized a novel bHLH-PAS factor 'NXF' as a new member of the mammalian bHLH-PAS family. If model animals have ortholog genes for NXF, they might have advantages for characterization of its function and regulation in vivo. Here we document cDNA cloning and characterization of putative NXF homolog genes (for NXF-like-factors) in Drosophila and C. elegans. Some conservation of the exon-intron gene architecture was noted in the bHLH-PAS domains among NXF-like-factors and human NXF. The NXF-like-factors selectively interacted with an Arnt ortholog in vitro assay. Moreover, they selectively associated with the mammalian NXF:Arnt2 binding element in the presence of the Arnt ortholog, and synergistically activated a mammalian NXF:Arnt-responsive promoter. These data strongly suggest that the Drosophila and C. elegans NXF-like-factors reported here are homologs of mammalian NXF. Further elucidation of whether they are true orthologs with the same function in vivo is now necessary.