The aim of the study was to define the relative importance of the various causes of neonatal deaths, to estimate the role of the associated risk factory, and to examine the extent to which neonatal deaths can be prevented. Four-hundred neonatal deaths from 284 families identified either in a prospective cohort of neonates referred for genetic assessment or retrospectively in families with history of one or more neonatal deaths were evaluated. The clinical cause of death for each case was assigned according to a modified Wigglesworth Classification. A control group of 400 health infants randomly selected from several Health Offices in Alexandria was included for comparison of the investigated risk factors for neonatal deaths. The most common causes of neonatal death were lethal malformation syndromes [24%], single birth defects [17.5%], and multiple congenital malformations [16%] with prematurity and low birth weight accounting for 15.5% of deaths, while 20% of the studied cases had no convincing explanation. Results confirmed a significant association between neonatal deaths and parental consanguinity, family history of genetic diseases, previous reproductive loss, maternal illnesses, and advanced maternal age. It is concluded that the incidence of lethal congenital malformations and premature/low birth weight infants must be impacted in order to reduce neonatal mortality rates. Spread of genetic counseling services with appropriate interventions as premarital counseling, good ante-natal care, and improving the management of low-birth-weight infants through better neonatal intensive care unit services all are recommended.