Phenytoin is frequently used to treat seizure episodes in critically ill patients. Some of these patients have acute renal failure, requiring continuous hemofiltration to help maintain fluid and solute balance. We evaluated the removal of phenytoin in patients who received the drug while undergoing continuous hemofiltration treatment. Arterial and ultrafiltrate sample pairs were collected for phenytoin concentration determination. The ultrafiltrate drug concentrations were almost identical to the free serum phenytoin concentrations. Thus the ultrafiltrate/arterial drug concentration ratios resembled the percentages of serum free drug. Between 0.32 and 0.78 mg of phenytoin/h was removed by hemofiltration. The magnitude of hemofiltration phenytoin removal was related to the free drug concentration, total serum drug concentration, and ultrafiltration flow rate. When the ultrafiltration flow rate was low, the amount of phenytoin removed by hemofiltration was small relative to the usual daily dose. However, in patients with renal failure in whom serum phenytoin protein binding is substantially reduced, continuous hemofiltration at a high ultrafiltration rate may remove a clinically significant amount of the drug. Higher daily doses of phenytoin may be needed to maintain the therapeutic effect. Serum drug concentration monitoring will be necessary to determine the optimal dosage regimen.