The incidence of seizures related to primary brain tumors is 20-80%. High-dose tamoxifen was recently reported as a novel treatment for patients with malignant gliomas who have failed standard therapies. Tamoxifen inhibits protein kinase C (PKC) in vitro and thus may regulate glioma cell growth by modulating intracellular signal transduction. We report a patient with a recurrent supratentorial pilocytic astrocytoma who had an untoward interaction between high-dose tamoxifen therapy and phenytoin (PHT), drugs that share a common enzyme for metabolism, therefore emphasizing the need to monitor concomitant antiepileptic drug (AED) levels when high-dose tamoxifen therapy is instituted.