Free phenytoin levels were determined in a group of patients with renal disease treated by hemodialysis or transplantation and in epileptic patients who were otherwise healthy. A highly significant correlation was observed between free drug levels and the phenytoin content of red blood cells in both groups. Considerable fluctuation in free phenytoin levels was observed during long-term maintenance hemodialysis. After transplantation, the degree of abnormality in plasma protein binding was not related to the functional adequacy of the cadaveric allografts. Free phenytoin levels must be monitored in patients with renal disease.