Painful episodes of sickle cell disease remain a source of frustration to patients and health care providers because of the lack of interventions to prevent or control them. Nalbuphine is a potent semisynthetic agonist/antagonist analgesic. We report our experience using nalbuphine as a treatment for painful episodes of sickle cell disease in children. The efficacy of subcutaneous/intramuscular nalbuphine is compared with intramuscular meperidine by a retrospective review of hospitalizations for sickle cell painful episodes. Nalbuphine is as effective as meperidine for the treatment of these episodes. We conclude that nalbuphine is a feasible and effective analgesic and a reasonable treatment option for patients with sickle cell disease experiencing painful episodes.