Adherence to antiretroviral therapy (ART) has markedly improved HIV disease management, and significantly reduced HIV/AIDS-associated morbidity and mortality. Although recent studies suggest a relationship between smoking and suboptimal adherence to ART, a more in-depth understanding of this relationship is needed. We conducted a secondary analysis using data from a randomized controlled smoking cessation trial to investigate the association of nonadherence to ART with potential demographic, psychosocial (perceived stress and depression), and substance use (nicotine dependence, illicit drug use, and alcohol use) variables among persons living with HIV/AIDS (PLWHA) who smoke. The mean (standard deviation [SD]) age of participants (n=326) was 45.9 years old (SD=7.6). Additionally, the majority were male (72.1%), self-identified as black (76.7%), and reported sexual contact as the mode of HIV acquisition (70%). Unadjusted logistic regression analysis indicated that depression (odds ratio [OR]=1.02; 95% confidence interval [CI]=1.00, 1.04), illicit drug use (OR=2.39; 95% CI=1.51, 3.79) and alcohol use (OR=2.86; 95%CI=1.79, 4.57) were associated with nonadherence. Adjusted logistic regression analysis indicated that nicotine dependence (OR=1.13; 95% CI=1.02, 1.25), illicit drug use (OR=2.10; 95% CI=1.27, 3.49), alcohol use (OR=2.50; 95% CI=1.52, 4.12), and age (OR=1.04; 95% CI=1.00, 1.07) were associated with nonadherence. Nicotine dependence, illicit drug use, and alcohol use are potentially formidable barriers to ART adherence among PLWHA who smoke. Future efforts should investigate the complex relationships among these variables to improve adherence particularly among populations confronted with multifaceted health challenges. © Copyright 2012, Mary Ann Liebert, Inc.