Patients with severe uremia may have a bleeding tendency associated with a prolonged bleeding time and an adequate platelet count. We have tested the effects on platelet aggregation of three compounds that are found in increased concentration in the blood of patients with renal failure. The addition of urea was followed by an immediate, but transient, increase in optical density of platelet-rich plasma. This precluded the use of turbidimetric techniques for the measurement of platelet aggregation after addition of urea, until the optical density became stable. Adenosine diphosphate-, collagen-, and norepinephrine-induced platelet aggregation were shown to be inhibited 1 hr after urea was added to platelet-rich plasma to produce urea nitrogen increments of 100-300 mg/ 100 ml. Increasing concentrations of creatinine by 10 or 20 mg/100 ml did not inhibit platelet aggregation. Guanidinosuccinic acid, in a concentration in the range found in uremic plasma, also had no effect on platelet aggregation. Through inhibition of platelet aggregation, elevated blood concentrations of urea may be one of the causes of the bleeding tendency of uremic platients.