Hematuria in patients with sickle cell trait might be related to sickling in the medullary vessels of the kidney. In vitro, hypertonicity, acidity, and anoxia may cause sickling. These conditions may also exist in the renal medulla of man. In two patients with long-standing hematuria associated with sickle cell trait, urinary hemoglobin loss consistently diminished or transiently stopped following urinary alkalinization or certain measures which theoretically diminish medullary tonicity and increase medullary oxygen tension. Transient cessation of hematuria also occurred repeatedly after an infusion of distilled water. This phenomenon may be related to red cell expansion and dilution of S-hemoglobin and supports experimental evidence that a critical concentration of S-hemoglobin is a prerequisite for sickling.