Objectives: We examined the association between perceived discrimination and smoking status and whether psychological distress mediated this relationship in a large, multiethnic sample. Methods: We used 2004 through 2008 data from the Behavioral Risk Factor Surveillance System Reactions to Race module to conduct multivariate logistic regression analyses and tests of mediation examining associations between perceived discrimination in health care and workplace settings, psychological distress, and current smoking status. Results: Regardless of race/ethnicity, perceived discrimination was associated with increased odds of current smoking. Psychological distress was also a significant mediator of the discrimination-smoking association. Conclusions: Our results indicate that individuals who report discriminatory treatment in multiple domains may be more likely to smoke, in part, because of the psychological distress associated with such treatment.