Background: Globally, India is the country with the highest tuberculosis (TB) burden with respect to the number of new cases occurring each year. Annual incident cases of TB in India accounts for more than 25% of total TB morbidity and mortality worldwide. Several factors have been associated with the adherence of TB medication, which can be broadly classified as patient/personal, social, structural and health service. The aims of the present study were to determine the compliance to daily regimen of directly observed treatment, short-course (DOTS) therapy among TB patients registered at the Tuberculosis Unit (TU) of Mangalore and to identify the factors influencing non-compliance for treatment. Methods: A cross sectional study was performed. The study sample was drawn from the TUs, General Hospital, Mangalore, after taking permission from District TB Officer. The names and addresses of TB patients were collected from treatment cards. The TB patients were approached at their homes/DOTS centers/Primary Health Centre's (PHCs) with the help of senior treatment supervisors. Results: It was found that patients positive for human immunodeficiency virus (HIV) were more likely to be non-adherent, which was statistically significant. Amongst the participants, 66 (33%) were diabetic and 28.8% of them were found to be non-adherent. The proportion of non-adherence was 27 times higher in those with poor patient provider relationships. Patients who reported to have side effects of TB medication were 5.23 times more likely to be non-adherent. Conclusions: Advice on routine consultation with the health care facility, adherence to treatment regimen and education about its benefits should be the prime focus of providing health education to all TB patients, both at the individual and community levels.