Excitotoxicity, oxidative stress, and apoptosis have been recognized as routes to neuronal death in various neurological diseases. We examined the possibility that PHF-1 tau, a substrate for various proteases, would be selectively cleaved depending upon routes of neuronal death. Cleavage form of PHF-1 tau was not observed in cortical cell cultures exposed to excitotoxins or oxidative stress that cause neuronal cell necrosis. PHF-1 tau was cleaved within 8 h following exposure of cortical cell cultures to apoptosis-inducing agents. This cleavage was blocked by inclusion of zDEVD-fmk, an inhibitor of caspase-3, and accompanied by activation of caspase-3. Levels and cleavage of PHF-1 tau were markedly increased in AD brain compared with control. Moreover, PHF-1 tau and active caspase-3 were colocalized mostly in tangle-bearing neurons. The current findings suggest that PHF-1 tau is cleaved by caspase-3 during apoptosis and neurodegenerative process in AD.