Major structural or genetic birth defects affect approximately 3% of births in the United States, are a major contributor to infant mortality, and result in billions of dollars in costs for care. Although the causes of most major birth defects are unknown, concerns have been raised that certain factors, such as an increase in the prevalence of diabetes among women, might result in increased prevalence of birth defects over time. This report updates previously published data from the Metropolitan Atlanta Congenital Defects Program (MACDP), the oldest population-based birth defects surveillance system in the United States with active case ascertainment. For the period 1978-2005, CDC assessed the overall prevalence of major birth defects and their frequency relative to selected maternal and infant characteristics. The MACDP results indicated that the prevalence of major birth defects in metropolitan Atlanta, Georgia, remained stable during 1978-2005 but varied by maternal age and race/ethnicity, birthweight, and gestational age. Tracking the overall prevalence of major birth defects can identify subgroups that are affected disproportionately; additional measures focused on these subgroups might improve preconception care and care during pregnancy to prevent birth defects.