The monoclonal antibody PHF-1 recognizes phosphorylated tau isoforms present in paired helical filaments of Alzheimer's disease. We have found that PHF-1 immunoreactivity is present in chick brain, which expresses three major PHF-1-reactive proteins at the same molecular weights seen in humans. The developmental pattern of expression suggests a functional role in differentiation, rather than in programmed nerve cell death. Expression of PHF-1 immunoreactivity in developing retina was highly cell selective, showing robust staining of ganglion cells, the only long-axon neuron of the seven major retina cell types. The majority of ganglion cells were PHF-1 positive. The developmental window of expression extended at least from E6 through P0, well outside the period of embryonic ganglion cell death. Mature cells did not show PHF-1 immunoreactivity. In the embryo, staining was particularly robust in ganglion cell axons (optic fiber layer), and association of PHF-1 reactivity with axonal tracts also was seen in developing forebrain. PHF-1 polarization occurred at ages when staining with polyclonal anti-tau did not show axonal selectivity. Similarly, in cell cultures, PHF-1 immunoreactivity became localized to single neurites, but polyclonal anti-tau did not. These results indicate that, rather than being associated with cell degeneration, PHF-1 immunoreactivity in the developing nervous system is associated with early stages of axon formation, both in vivo and in vitro. Therefore, expression of PHF-1 immunoreactive proteins in Alzheimer's disease suggests that paired helical filament formation might be triggered by mechanisms related to axon regeneration.