Genome-wide association (GWA) genetic epidemiology research has identified several variants modestly associated with brief self-report smoking measures, predominately in European Americans. GWA research has not applied intensive laboratory-based measures of smoking endophenotypes in African Americans-a population with disproportionately low quit smoking rates and high tobacco-related disease risk. This genetic epidemiology study of non-Hispanic African Americans tested associations of 89 genetic variants identified in previous GWA research and exploratory GWAs with 24 laboratory-derived tobacco withdrawal endophenotypes. African American cigarette smokers (N = 528; ≥10 cig/day; 36.2% female) completed two counterbalanced visits following either 16-hr of tobacco deprivation or ad libitum smoking. At both visits, self-report and behavioral measures across six unique "sub-phenotype" domains within the tobacco withdrawal syndrome were assessed (Urge/Craving, Negative Affect, Low Positive Affect, Cognition, Hunger, and Motivation to Resume Smoking). Results of the candidate variant analysis found two significant small-magnitude associations. The rs11915747 alternate allele in the CAD2M gene region was associated with .09 larger deprivation-induced changes in reported impulsivity (0-4 scale). The rs2471711alternate allele in the AC097480.1/AC097480.2 gene region was associated with 0.26 lower deprivation-induced changes in confusion (0-4 scale). For both variants, associations were opposite in direction to previous research. Individual genetic variants may exert only weak influences on tobacco withdrawal in African Americans. Larger sample sizes of non-European ancestry individuals might be needed to investigate both known and novel loci that may be ancestry-specific. (PsycInfo Database Record (c) 2022 APA, all rights reserved).