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Background Tuberculosis (TB) control efforts are often ineffective in controlling TB among patients who use illicit drugs or abuse alcohol (substance abuse). This study examined the prevalence of substance abuse among TB cases reported in the United States and assessed the relation between substance abuse and indicators of TB transmission. Methods A cross-sectional analysis was performed of data on US TB cases in patients 15 years or older reported from 1997 through 2006. Analyses included number and proportion of patients with TB characterized by substance abuse and associations between substance abuse, sputum smear status, treatment failure, and inclusion in a county-level genotype cluster. Results Of 153 268 patients with TB, 28 650 (18.7%) reported substance abuse, including 22 293 of 76 816 US-born patients (29.0%). Multivariate analysis showed that, among patients negative for human immunodeficiency virus, odds of sputum smear–positive disease were 1.8 (99% confidence interval [CI], 1.7-1.9) times greater among those who reported substance abuse; this association was weaker among patients with human immunodeficiency virus infection (odds ratio [OR], 1.2; 99% CI, 1.1-1.4). Among female patients, odds of treatment failure were 2.4 (99% CI, 1.9-3.0) times greater among those who reported substance abuse. The association was weaker among male patients (OR, 1.5; 99% CI, 1.3-1.7). Patients who abused substances were more likely to be involved in a county-level genotype cluster (US-born: OR, 2.3; 99% CI, 2.0-2.7; foreign-born: 1.5; 1.2-2.0). Conclusions Substance abuse is the most commonly reported behavioral risk factor among patients with TB in the United States. Patients who abuse substances are more contagious (eg, smear positive) and remain contagious longer because treatment failure presumably extends periods of infectiousness. Increased transmission is consistent with our finding that patients who abuse substances were more likely to be involved in a localized genotype cluster, which can represent recent transmission.