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In this study, the authors identified maternal and child characteristics that were independent predictors of death from infectious diseases acquired in the community and determined if these factors could be used to identify groups of children with excess risk of mortality from infection. A historical cohort study was conducted of children less than 5 years of age between 1985 and 1994 (the study period), who were born in Tennessee, and had complete information on their birth certificates. The primary outcome was death from infection identified from death certificates and confirmed through medical record review. Among the 1,014,976 children less than 5 years of age, who contributed 3,351,568 child-years of follow-up, there were 247 deaths from infections (7.4 deaths from infections per 100,000 child-years). Respiratory infections accounted for approximately one half of the deaths. Children having three or more older siblings or birth weight of less than 1,500 g had a 3-fold and 10-fold increased risk of death from infection, respectively, while children with both characteristics had a nearly 20-fold increased risk that persisted beyond the first year of life. Interventions should be focused on prevention of these infections in vulnerable children. At-risk children should be targeted for careful follow-up and early hospitalization when signs of infection develop.