Background. Infant mortality in the United States has continued to decline in recent years, but changes in sepsis-associated deaths among infants have not been evaluated previously. Methods. Data from US death records were analyzed for the period 1979 through 1994 to assess trends in sepsis-associated deaths among newborns and older infants. Results. Annual neonatal mortality associated with sepsis declined by 25% from 50.5 deaths per 100 000 live births in 1979 through 1981 to 38.0 deaths per 100 000 live births in 1992 through 1994. Although infant mortality associated with sepsis declined from 71.7 to 56.4 per 100 000 live births over the same period, this decline was attributable to lower sepsis-related mortality among newborns. The rates of sepsis-associated deaths declined for both preterm and term deliveries. Approximately 2260 infants (1521 of whom were newborns) died of sepsis per year in 1992 through 1994. Sepsis-associated death was more likely to occur among infants who were male, black, preterm, or born in the South. Among black infants, the racial gap in sepsis-associated mortality was greater for term than for preterm infants. Conclusions. Despite declines in the overall sepsis-related mortality among newborns, racial and regional gaps in mortality persisted over the 16-year study period. Almost half of the sepsis-related deaths occurred among infants who were born prematurely. Disproportionate rates of prematurity among blacks and infants born in the South may have contributed to persistently high sepsis-related mortality in these groups. Future efforts to reduce the incidence of sepsis-associated deaths will depend on targeting higher risk populations and reducing prematurity.