Serum uric acid and uric acid excretion were studied in 95 patients with sickle cell anemia ranging in age from 17 months to 45 years to ascertain the natural history of urate overproduction. Hyperuricemia was infrequent in children with sickle cell anemia, but was found in 26 of 67 adults (39%). Thirty-six patients studied in a clinical research center had a mean urate clearance of 9.1 ± 0.8 mL/min. Patients with sickle cell anemia were often normouricemic despite urate overproduction. Normouricemia was maintained by increased urate clearance, which was attributed to increased urate secretion. The hyperuricemic patients had decreased urate clearance with decreased pyrazinamide-suppressible urate clearance. Para-aminohippurate clearance was decreased to 634 mL/min in the hyperuricemic patients with sickle cell anemia compared with 853 mL/min in normouricemic hyperuricosuric subjects with sickle cell anemia. Hyperuricemia occurs only in patients who develop altered renal tubular function with diminished urate clearance secondary to diminished urate secretion.