FHF2A and FHF2B are two members of the fibroblast growth factor homologous factor 2 (FHF2) subfamily with distinct N termini. Using a generic antibody and electrophysiological methods, we previously showed that FHF2 is expressed in hippocampus and dorsal root ganglion (DRG) neurons and is colocalized with sodium channel Na(v)1.6 at sensory but not motor nodes of Ranvier, and that FHF2B associates with Na(v)1.6, causing an increase in current density and a small depolarizing shift in availability of channels. Using immunolabeling of adult rat tissue, we demonstrate that FHF2A is present within DRG but not in hippocampal or cerebellar neurons or at nodes of Ranvier in sciatic nerve, and that Na(v)1.6 and FHF2A are colocalized in nonmyelinated fibers. We also show that FHF2A binds directly to Na(v)1.6, and that the two proteins coimmunoprecipitate from transfected HEK293 cells. Because Na(v)1.6 has been associated with rapid firing rates, we examined the possible effects of FHF2B and the sister isoform, FHF2A, on electrophysiological properties of this channel in the DRG-derived ND7/23 cell line. We show that FHF2B inhibits accumulation of inactivation in response to trains of stimulation at high frequencies. In marked contrast, FHF2A causes an accumulation of inactivated channels at all frequencies tested due to a slowing of recovery from inactivation. Thus different FHF2 subfamily members have different functional effects on Na(v)1.6 and are differentially distributed in DRG neurons and their axons. This suggests that FHF2A and FHF2B may selectively alter firing behaviour of specific neuronal compartments via differential modulation of Na(v)1.6.