OBJECTIVE: To describe changes in the epidemiology of multiple births in the United States from 1980 to 1999 by race, maternal age, and region; and to examine the impact of these changes on birth weight-specific infant mortality rates for singleton and multiple births. METHODS: Retrospective univariate and multivariable analyses were conducted using vital statistics data from the National Center for Health Statistics. RESULTS: Between 1980 and 1999, the overall multiple birth ratio increased 59% (from 19.3 to 30.7 multiple births per 1000 live births, P < .001), with rates among whites increasing more rapidly than among blacks. Women of advanced maternal age, especially those aged 30–34, 35–39, and 40–44 experienced the greatest increases (62%, 81%, and 110%, respectively). Although all regions of the United States experienced increases in multiple birth ratios between 1991 and 1999, the Northeast had the highest twin (33.9 per 1000 live births) and higher order birth ratios (280.5 per 100,000 live births), even after adjusting for maternal age and race. Between 1989 and 1999, multiple births experienced greater declines in infant mortality than singletons in all birth weight categories. Consequently, very low birth weight and moderately low birth weight infant mortality rates among multiples were lower than among singletons. CONCLUSION: It is important to understand the changing epidemiology of multiple births, especially for women at highest risk (advanced maternal age, white race, Northeast residents). The attribution of infertility management requires further study. The differential birth weight-specific infant mortality for singletons and multiples demonstrates the importance of stratifying by plurality when assessing perinatal outcomes.