Objectives: In this study, we investigated the determinants of poor adherence with anti-tuberculosis therapy among pulmonary tuberculosis (TB) patients in Mumbai, India, receiving Directly Observed Treatment Short Course (DOTS) therapy. Methods: A cross-sectional study on 538 patients receiving DOTS I and II regimen was conducted. Patients were interviewed and clinical and laboratory data were collected. Eighty seven patients were considered non-adherent. Multivariable logistic regression was used to determine risk factors associated with non-adherence. Results: Factors associated with non-adherence were found to be different among the newly-diagnosed patients and all the other residual groups. Smoking during treatment and travel-related cost factors were significantly associated with non-adherence in the newly-diagnosed patients, while alcohol consumption and shortage of drugs were significant in the residual groups. Conclusions: An approach, targeting easier access to drugs, an ensured drug supply, effective solutions for travel-related concerns and modification of smoking and alcohol related behaviors are essential for treatment adherence.