© 2019 Wiley Periodicals, Inc. Objectives: We investigated differences in prevalence of major birth defects by maternal nativity within racial/ethnic groups for 27 major birth defects. Methods: Data from 11 population-based birth defects surveillance systems in the United States including almost 13 million live births (approximately a third of U.S. births) during 1999–2007 were pooled. We calculated prevalence estimates for each birth defect for five racial/ethnic groups. Using Poisson regression, crude and adjusted prevalence ratios (aPRs) were also calculated using births to US-born mothers as the referent group in each racial/ethnic group. Results: Approximately 20% of case mothers and 26% of all mothers were foreign-born. Elevated aPRs for infants with foreign-born mothers were found for spina bifida and trisomy 13, 18, and 21, while lower prevalence patterns were found for pyloric stenosis, gastroschisis, and hypospadias. Conclusions: This study demonstrates that birth defects prevalence varies by nativity within race/ethnic groups, with elevated prevalence ratios for some specific conditions and lower prevalence for others. More detailed analyses focusing on a broader range of maternal behaviors and characteristics are required to fully understand the implications of our findings.