Chronic hypoxemia is a common manifestation among patients with sickle cell anemia (SCA) who develop chronic lung disease. We report the beneficial effect of hydroxyurea on chronic hypoxemia in three pediatric patients with SCA and recurrent episodes of acute chest syndrome (ACS). All three patients improved rapidly after they were treated with hydroxyurea despite having additional risk factors for hypoxemia. A prospective trial is warranted to assess whether there is a therapeutic effect from the use of hydroxyurea in pediatric SCA patients with chronic hypoxemia. Pediatr Blood Cancer 2008;50:1258–1260. © 2008 Wiley-Liss, Inc.