Aim: Multidrug-resistant tuberculosis (MDR-TB) arises where treatment is interrupted or inadequate, when patients are treated inappropriately, or when an individual has impaired immune function, which can lead to a rapid progression from infection with an MDR-strain to disease. This study examines the role of health systems in amplifying or preventing the development of MDR-TB.Methods: We present two comparative studies, which were undertaken in The Former Yugoslav Republic of Macedonia (TFYR Macedonia) and Moldova.Results: The findings reveal several health systems-level factors that contribute to the different rates of MDR-TB observed in these two countries, including: pre-existing burden of disease; organization of the health system, with the existence of parallel systems; power dynamics among policy makers and disease programmes; and the accountability & effectiveness of programme oversight.Conclusions: The findings do not offer a universal template for health system reform but do identify specific factors that may be contributing to the epidemic and are worthy of further attention in the two countries.