Fosphenytoin is a prodrug that is metabolized by phosphatases to yield the antiepileptic drug phenytoin plus inorganic phosphate. Thus, fosphenytoin can theoretically alter the electrocardiogram by 2 mechanisms: the direct effects of phenytoin on cardiac conduction and on phosphate binding of calcium, which could indirectly alter cardiac conduction as a result of hypocalcemia. We report the case of a 23-year-old man, weight 73 kg, with a known but untreated seizure disorder who was given prophylactic fosphenytoin, 1500-mg phenytoin equivalents over 85 minutes by intravenous infusion. The patient was normocalcemic before drug infusion. Fosphenytoin produced electrocardiographic changes (prolongation of the ST segment and the QT interval and merging of the T and P waves) consistent with hypocalcemia, and these changes were associated with new-onset reductions in both total and ionized serum calcium concentrations. Plasma phenytoin concentrations were within the therapeutic range during the electrocardiographic changes, and the patient's blood pressure was stable. We interpret these findings as fosphenytoin-related electrocardiographic changes likely attributable to inorganic phosphate-induced hypocalcemia.