Neonatal mortality due to congenital malformations or genetic disorders has not decreased despite a decrease in overall neonatal deaths with recent advances in medical technology. As a consequence, an increasing percentage of neonatal deaths is attributable to congenital malformations and genetic disorders. This study retrospectively reviewed neonatal deaths associated with congenital malformations over an 11-year period in the neonatal intensive care unit (NICU) at Kosair Children's Hospital, Louisville, Kentucky. Presently, congenital malformations are responsible for approximately 45% (range 32% to 61%) of deaths in the NICU with congenital heart disease, lethal genetic disorders, and pulmonary hypoplasia being the main contributors. Other major causes of neonatal death included extreme prematurity, respiratory disorders, necrotizing enterocolitis, sepsis, asphyxia, and primary pulmonary hypertension. It is important that clinicians are aware that improved survival is expected for most diseases because of technological advances, but that further significant reductions in neonatal mortality will depend on genetic counseling and prevention of congenital malformations.