Achieving and maintaining the proper balance between detecting fetuses with open spina bifida or Down syndrome while maintaining an acceptably low screen-positive rate requires careful, ongoing monitoring of screening performance indicators along with specific procedures aimed at taking rapid and effective corrective actions when warranted. The process of epidemiologic monitoring, which uses data generated from the screened population, has been developed as an extended quality assurance measure for this purpose. The primary indicators used include the percentage of women with a screen-positive result and the grand multiple of the median. These indicators are sensitive to inaccurate and imprecise assay values and help to ensure that gestational age-specific median values are appropriate. Epidemiologic monitoring also provides useful information for physicians, public health authorities, and regulatory bodies.