Introduction: The animal and human research literatures suggest that deprived environmental conditions may be associated with drug dependence, but the relation of neighborhood perceptions with a multidimensional measure of tobacco dependence has not been previously studied. The purpose of this study was to examine the associations between neighborhood perceptions (neighborhood problems and neighborhood vigilance) and tobacco dependence among smokers as measured by the Wisconsin Inventory of Smoking Dependence Motives-68 (WISDM). Methods: Participants were 384 African American smokers (49% men, 80% <$30,000 annual household income) enrolled in a randomized clinical trial of a smoking cessation intervention. A series of regression models were conducted to examine the associations between neighborhood perceptions and tobacco dependence using a generalized estimating equation approach, which accounted for potential correlation in tobacco dependence between participants from the same neighborhood. Results: Results indicated that more self-reported neighborhood problems and greater neighborhood vigilance were significantly associated with tobacco dependence as measured by the WISDM total score in analyses adjusted for age, gender, income, education, employment status, and partner status (p ≤ .002). Neighborhood perceptions were related to both primary and secondary dependence motives (p ≤ .005). Conclusions: Results suggest that the neighborhood context is associated with dependence on tobacco among African American smokers but longitudinal studies are needed to assess causation. Future research should also explore the mechanisms that account for the associations between neighborhood perceptions and tobacco dependence to better inform intervention development.