Investigators have reported that certain metabolic disorders (fatty acid oxidation (FAO) disorders and organic acidemias) contribute to unexpected early childhood deaths. We estimated the contribution of these metabolic disorders to a population-based sample of unexpected early childhood deaths. The study population included children less than 3 years of age who died during 1996-2001 and whose deaths were investigated by the Virginia Office of the Chief Medical Examiner (ME). Dried post-mortem blood on filter paper was sent to a reference laboratory for metabolic screening by tandem mass spectrometry. When molecular DNA analysis was available to identify known gene mutations, positive screens were confirmed. If molecular DNA analysis for a suspected disorder was not available, tandem mass spectrometry was performed on newborn blood spots when available. If DNA analysis was not available and newborn blood spots could not be obtained, an independent expert biochemical geneticist confirmed the post-mortem interpretation. We obtained screening results for 793 (88%) of 904 children examined. Eight children had a positive screen for FAO disorders or organic acidemias. One child would not have benefited from identification in the newborn period. However, seven children's outcomes might have been improved had they been identified during the newborn period and effectively treated. Post-mortem metabolic screening may identify a cause of death for about 1% of children who die unexpectedly before 3 years of age, allowing for identification and treatment of affected siblings. Identifying and treating affected children during the newborn period may offer an opportunity to reduce early childhood mortality.