This study aimed to evaluate the risk factors for tuberculosis (TB) treatment default in a priority city for disease control in Brazil. A cohort of TB cases diagnosed from 2008 to 2009 was followed up from patients’ entry into three outpatient sites, in Juiz de Fora, Minas Gerais (Brazil), until the recording of the outcomes. Drug addiction, alcoholism and treatment site appeared to be independently associated with default. Current users of crack as the hardest drug (odds ratio (OR) 12·25, 95% confidence interval (CI) 3·04–49·26) were more likely to default than other hard drug users (OR 5·67, 95% CI 1·34–24·03), former users (OR 4·12, 95% CI 1·11–15·20) and those not known to use drugs (reference group). Consumers at high risk of alcoholism (OR 2·94, 95% CI 1·08–7·99) and those treated in an outpatient hospital unit (OR 8·22, 95% CI 2·79–24·21%) also were more likely to default. Our results establish that substance abuse was independently associated with default. National TB programmes might be more likely to achieve their control targets if they include interventions aimed at improving adherence and cure rates, by diagnosing and treating substance abuse concurrently with standard TB therapy.