A number of compounds known to accumulate in the blood of uremic patients were added to serum from healthy normal volunteers. It was observed that both hippuric acid and indican were capable of increasing substantially the serum f of both diazepam and warfarin. Furthermore, a mixture of nine different accumulation products (many of which did not measurably increase f when added alone) caused an even greater increase in the f of diazepam. Serum from uremic patients and from normal volunteers, with and without the addition of the compounds known to accumulate in uremia, wee treated by standard procedures (i.e., prolonged dialysis, charcoal treatment, pH alteration) to remove associated small molecules. The results of such treatments suggest that at least part of the diminished binding of drugs seen in the presence of uremia is due to the accumulation of low-molecular-weight endogenous competitors.