Objective: Prospective data tested a “differential mediation” hypothesis: The relations (found in previous research) between perceived racial discrimination and physical health status versus health-impairing behavior (problematic substance use) are mediated by two different types of affective reactions, internalizing and externalizing. Method: The sample included 680 African American women from the Family and Community Health Study (M age = 37 years at Time 1; 45 years at Time 4). Four waves of data were analyzed. Perceived discrimination was assessed, along with anxiety and depression (internalizing) and hostility/anger (externalizing) as mediators, and physical health status and problematic substance use (drinking) as outcomes. Results: Structural equation modeling indicated that discrimination predicted increases in both externalizing and internalizing reactions. These affective responses, in turn, predicted subsequent problematic substance use and physical health status, respectively, also controlling for earlier reports. In each case, the indirect effects from discrimination through the affective mediator to the specific health outcome were significant and consistent with the differential mediation hypothesis. Conclusions: Perceived racial discrimination is associated with increases in internalizing and externalizing reactions among Black women, but these reactions are related to different health outcomes. Changes in internalizing are associated with self-reported changes in physical health status, whereas changes in externalizing are associated with changes in substance use problems. Discussion focuses on the processes whereby discrimination affects health behavior and physical health status.