In metropolitan France, newborn screening for sickle cell disease has been performed at the Hĵpital Henri Mondor, Créteil, since 1985. After confirmation of the diagnosis, children are enrolled in a comprehensive medical-care program. Our aim was to evaluate the effectiveness of this program in France where most families are first generation immigrants with cultural and social differences that can interfere with medical follow-up. We compared the complications of sickle cell disease in two populations of homozygous SS children aged more than two years at their last medical visit, and recruited from an initial register of 134 SS children: (1) 38 diagnosed by neonatal screening; (2) 69 controls, diagnosed at a mean age of 24 months. Mean age at the last medical visit is 58 months in both groups. Splenic sequestrations and painful crises were significantly reduced in the screened group. Two screened children, belonging to the initial register from which the 38 other screened children were collected, died from overwhelming infection at 15 and 23 months, respectively. Neonatal diagnosis of sickle cell disease, coupled with specific preventive measures may lead, in the initial six years of life, to reduced painful events and splenic sequestration episodes. Education of parents is one of the hallmarks of preventive measures and may be difficult in first generation immigrants. Because of the bias of this type of study, a large prospective follow-up since birth is necessary to have a better understanding of the clinical course.