This study explores mediating medical risk factors in the association between racial residential segregation (i.e., racial 'black' isolation) and low birthweight in New York City, adjusting for maternal and infant risk factors and neighborhood poverty. This race-specific cross-sectional multilevel study found that as racial isolation increased in neighborhoods, the odds of having a low birthweight infant also increased for African-American and White women living in these areas. Medical conditions that mediated the racial isolation and low birthweight relationship included chronic hypertension and pregnancy-related hypertension for African-American women and chronic hypertension and lung disease for White women. Although this study was limited by the quality of the birth certificate data, it does provide exploratory pathways by which medical risks and their sequelae are linked to neighborhood environments and reproductive vulnerability.