Tuberculosis (TB) remains a major health problem in Argentina with consistently below recommended success rates of 53-66%, between 1998 to 2005, compared to the WHO Stop TB program target to successfully treat 85% of the cases. There are more than 10,000 new TB cases per year in Argentina, 48% are concentrated in the province of Buenos Aires and only 37% received direct observation of treatment (DOT). It is not well understood why DOT is being applied at low rates or how DOT compares to other treatment strategies when controlling for specific patient and health care facility (HCF) factors. Studies investigating treatment success tend to evaluate treatment strategies retrospectively or prospectively with patients divided into treatment groups without controlling for individual or HCF factors that may significantly impact on treatment outcome. Because of the complexity of treatment success in a given population, this study proposes a design that will prospectively assess factors and predictors, which traditionally have been studied in cross-sectional studies. Objectives: To assess the effectiveness of treatment regimens (DOT or SAT) and the impact of patient and HCF level factors on treatment outcomes defined as success (cure or completion of treatment) and default in pulmonary TB patients in high burden departments of Buenos Aires, Argentina. Design: Built upon a sequential mix-method (Qualitative/Quantitative) design, we designed a prospective study to follow up a cohort of 1100 patients with first diagnosis of pulmonary TB initiating treatment at select HCF to treatment completion. Methods: The study will be conducted in 40 HCF in Buenos Aires. Patients will be followed from initiation of treatment using TB assessment cards and a survey administered at recruitment. Treatment outcomes will be assessed at the end of the two month intense treatment phase and at treatment completion. Analysis: Data will be analyzed using multilevel regression modeling to estimate 1) the association between treatment strategy and individual patient and HCF level factors with treatment outcomes, 2) the proportion of variability of outcomes attributable to patient and HCF levels and 3) identify modifiable factors that can be applied to interventional studies to optimize resource allocations and impact policy. Significance: Treatment success hinges on a multitude of challenging, dynamic and complex factors, and, although connected, not just on DOT vs. Non-DOT. Identifying barriers to DOT implementation, evaluating risk factors at the individual patient level and system level and the effectiveness of treatment strategies will provide essential information. Results of the present study will provide information necessary to improve the organization of the programs, design feasible and context relevant interventions to achieve treatment success and optimize the effectiveness of TB control strategies in Argentina and in Latin America. PUBLIC HEALTH RELEVANCE: This study is relevant to public health departments with high tuberculosis (TB) burden, the National Tuberculosis Program of Argentina, the general public and tuberculosis programs in other countries. Understanding barriers to directly observed treatment (DOT) implementation, assessing effectiveness of the treatment strategies and identifying patient and health care facility factors to inform interventional studies are necessary steps to improve treatment success to achieve recommended rates of success.