KwaZulu-Natal has a high burden of tuberculosis disease, and is currently not meeting national and international treatment outcome targets. The aim of this study was to investigate patient-related and socio-economic factors that affect treatment adherence in patients on tuberculosis treatment in uMgungundlovu Health District. A case-control study design was used. Three hundred cases (treatment interruption) and 300 controls (treatment completed) were interviewed by trained fieldworkers using a structured questionnaire. In bivariate analysis, lack of education, unemployment and other socio-economic indicators (low income, type of housing, sanitation and residential area) were associated with an increased risk of treatment interruption. Personal factors [smoking, drug and alcohol use, human immunodeficiency virus (HIV) co-infection and perceived severity of illness] were also risk factors for treatment interruption. In multivariate analysis, distance from the clinic was significantly associated with treatment interruption [adjusted odds ratio (OR) 1.3, 95% confidence interval (CI): 1.3-1.6, p-value<0.005)], as well as residing in a rural area (adjusted OR 14, 95% CI: 1.1-18, p-value<0.005). Patients co-infected with HIV were twice as likely to interrupt treatment (adjusted OR 2.3, 95% CI: 1.1-4.7, p-value<0.005), and feeling very or fairly ill during tuberculosis treatment was also significantly associated with treatment interruption (adjusted OR 5.0, 95% CI: 2.1-11.9, p-value<0.005). The results highlight the complex interaction between personal and socio-economic risk factors for treatment interruption.