Approximately 10% of African-American women smoke during pregnancy compared to 16% of White women. While relatively low, the prevalence of smoking during pregnancy among African-American women exceeds the Healthy People 2010 goal of 1%. In the current study, we address gaps in extant research by focusing on associations between racial/ethnic residential segregation and smoking during pregnancy among urban African-American women. We linked measures of segregation to birth certificates and data from the 2000 census in a sample of US-born African-American women (n = 403,842) living in 216 large US Metropolitan Statistical Areas (MSAs). Logistic regression models with standard errors adjusted for multiple individual observations within MSAs were used to examine associations between segregation and smoking during pregnancy and to control for important socio-demographic confounders. In all models, a u-shaped relationship was observed. Both low segregation and high segregation were associated with higher odds of smoking during pregnancy when compared to moderate segregation. We speculate that low segregation reflects a contagion process, whereby salutary minority group norms are weakened by exposure to the more harmful behavioral norms of the majority population. High segregation may reflect structural attributes associated with smoking such as less stringent tobacco control policies, exposure to urban stressors, targeted marketing of tobacco products, or limited access to treatment for tobacco dependence. A better understanding of both deleterious and protective contextual influences on smoking during pregnancy could help to inform interventions designed to meet Healthy People 2010 target goals.