Optimizing health systems to improve delivery of decentralized care for patients with drug resistant tuberculosis Tuberculosis is a disease of the poor and remains a significant cause of disease and death globally. Our failure to effectively control the TB epidemic has resulted in the emergence of TB bacteria that have become resistant to the main drugs we use in treatment. These drug-resistant bacteria (DR-TB) can then be transmitted to others. In some settings DR-TB has now reached epidemic levels. While treatment is available, it's lengthy, complicated, expensive, and results in poor patient outcomes.  South Africa has a high burden of DR-TB, with more than 26,000 cases reported in 2013. Data suggest that a third of these patients do not have access to appropriate treatment, with only 40% cure for the rest. Fortunately, there are some recent advances that could assist in combatting the DR-TB epidemic. A rapid diagnostic test for DR-TB has been marketed and has now been rolled out across South Africa. This test (Xpert) has increased the number of patients identified and reduced the delay in receiving the diagnostic result. In addition, a new drug for treating DR-TB has just been registered in South Africa. Bedaquiline has the potential to dramatically improve the effectiveness of DR-TB treatment.  However, DR-TB diagnosis and treatment needs to be delivered in the context of the existing health system, the characteristics of which are likely to influence the impact of new interventions. In order to increase access to DR-TB treatment, South Africa moved to a policy of decentralized treatment provision in 2011, i.e., providing DR-TB treatment at lower levels of the health system, with less reliance on hospital treatment. This policy has been variably implemented across different provinces, health districts and settings (i.e., rural versus urban) in South Africa.   In order to maximize the benefit of new interventions, we aim to assess health system factors that enhance or undermine the delivery of treatment for DR-TB, specifically in regard to decentralization of care. We aim to determine what works and why it works, across different settings. Health system factors include such things as: the allocation of appropriate (number and training) human resources, financing at appropriate levels, organizational management, efficient communication and referral systems, sufficient inpatient capacity and access to other services needed for the care of DR-TB patients. These health system factors determine whether individuals with DR-TB disease access care, how long this takes, the quality of care they access, whether they transmit their infection to others and finally whether they have a successful treatment outcome or not. Ultimately, our findings will be used to identify feasible and effective strategies to improve decentralized care for patients with DR-TB in South Africa and other similar settings. The Global Challenges Research Fund (GCRF) supports cutting-edge research to address challenges faced by developing countries. The fund addresses the UN sustainable development goals. It aims to maximise the impact of research and innovation to improve lives and opportunity in the developing world.