Hyperphosphorylation of the microtubule‐associated protein τ is a characteristic of Alzheimer brain tissue. Recent in vitro data suggest that mitogen‐activated protein kinase (MAPK), a proline‐directed protein kinase, phosphorylates the sites on τ common to Alzheimer's disease. Using an okadaic acid‐induced τ hyperphosphorylation model, we have tested the requirement for MAPK activity, using a specific inhibitor {PD098059 [2‐(2′‐amino‐3′‐methoxyphenyl)oxanaphthalen‐4‐one]} of the MAPK activator Mek1. Mobility shift, phosphoepitope analysis, and direct measurement of kinase activity indicated that the Mek1 inhibitor dose‐dependently blocked basal and okadaic acid‐induced MAPK activation. Despite a block of MAPK activation by this inhibitor, robust τ hyperphosphorylation was observed in response to okadaic acid. In addition, activation of MAPK by phorbol 12‐myristate 13‐acetate did not result in τ phosphorylation, indicating that in primary cultures of cortical neurons elevated MAPK activity is not sufficient to induce τ hyperphosphorylation.