Proteinuria in children with sickle cell anemia (SCA) is an early sign of sickle nephropathy, and portends the development of nephrotic syndrome and chronic renal failure. Enalapril has been shown to reduce proteinuria in adult patients with SCA, but the potential benefits of hydroxyurea in this clinical setting have not been reported. A single institution retrospective analysis was performed. Children with sickle nephropathy were identified, and the laboratory effects of enalapril and hydroxyurea therapy were evaluated in children with substantial proteinuria. Three children developed proteinuria at 8 ± 1 years of age. Pre-treatment laboratory studies included a low serum albumin (2.8 ± 0.8 g/dl) and a highly elevated urine protein/creatinine ratio (6.9 ± 3.7, normal <0.2). Enalapril treatment for 3.0 ± 1.3 years normalized serum albumin (3.9 ± 0.3 g/dl) without significant changes in serum potassium, serum creatinine, or systolic blood pressure. However, urine protein/creatinine remained elevated in the nephrotic range (1.6 ± 0.7). The addition of hydroxyurea therapy for 3.5 ± 1.2 years increased fetal hemoglobin levels (7.0 ± 3.6% to 21.0 ± 3.2%) and was associated with a near-normal urine protein/creatinine ratio (0.5 ± 0.1). Enalapril therapy for children with sickle nephropathy reduces urinary protein excretion and normalizes serum albumin. Hydroxyurea therapy may further normalize the urine protein/creatinine ratio. Combination therapy should be tested prospectively in children with sickle nephropathy. © 2005 Wiley-Liss, Inc.