During the 20th century, U.S. infant mortality rates (IMRs) declined by 90%; however, many of the largest U.S. cities continue to have high IMRs compared with national rates. Studies of U.S. infant mortality by region document persisting geographic disparities and differences across racial/ethnic groups. This report highlights the wide disparities in the most recent overall race- and ethnicity-specific IMRs for the largest U.S. cities and describes key differences among those cities. The findings demonstrate the need to decrease infant mortality among blacks in U.S. cities.