The temporal association between oxidative stress and the hallmark pathologies of Alzheimer disease (AD) demonstrates that oxidative stress is among the earliest events in the disease. Nonetheless, neither the consequences of oxidative stress nor how oxidative stress relates to other pathological features of the disease are clear at this point. To begin to address these issues, we investigated p38 kinase, which is induced by oxidative stress, in the pathogenesis of AD. In hippocampal and cortical brain regions of individuals with AD, p38 is exclusively localized in association with neurofibrillar pathology. By marked contrast, these brain regions exhibit a low level of diffuse p38 staining in the neuronal cytoplasm in controls. We found a complete overlap of the immunostaining profiles of p38 and tau-positive neurofibrillary pathology and that the majority of p38 was activated in AD neurons, both of which support an association of p38 with the disease process. Moreover, the finding that PHF-tau co-immunoprecipitates with p38, and that p38 co-purifies with PHF-tau, strongly suggests that they are physically associated in vivo. Since p38 is also implicated in cell cycle regulation, our findings provide a link between the cell cycle re-entrant phenotype, cytoskeletal phosphorylation and oxidative stress in AD.