To assess the impact of newborn screening (NBS) on the mortality of children with sickle cell anemia, we analyzed the Connecticut death certificates of all children less than 15 years old at death. We compared sickle cell-related deaths in three periods: 1970-1988 when there was no state NBS; between 1988 and 1990 when there was limited state NBS; and 1990-2002 when universal NBS was in effect in Connecticut. In the period 1988-2002, we identified all death certificate records in which sickle cell anemia was listed as a cause of death and compared these with children who were shown to have sickle cell anemia (Hb SS and sickle-beta(o) thalassemia) by the state's NBS programs. In the 11-1/2 years after universal NBS was initiated in Connecticut in 1990, there were no reported deaths among infants diagnosed at birth with Hb SS or sickle-beta(o) thalassemia. In the 18 years before any State NBS (1970-1988) there were 13 deaths attributed to sickle cell diseases. The limited State NBS program conducted between 1988 and July 2000 missed testing five affected children who subsequently died. These results document a marked reduction in mortality since the introduction of NBS for hemoglobinopathies and suggest that the Connecticut NBS program, coupled with comprehensive follow-up care, greatly reduced mortality.