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Background Rabies is a notoriously underreported and neglected disease of low-income countries. This study aims to estimate the public health and economic burden of rabies circulating in domestic dog populations, globally and on a country-by-country basis, allowing an objective assessment of how much this preventable disease costs endemic countries. Methodology/Principal Findings We established relationships between rabies mortality and rabies prevention and control measures, which we incorporated into a model framework. We used data derived from extensive literature searches and questionnaires on disease incidence, control interventions and preventative measures within this framework to estimate the disease burden. The burden of rabies impacts on public health sector budgets, local communities and livestock economies, with the highest risk of rabies in the poorest regions of the world. This study estimates that globally canine rabies causes approximately 59,000 (95% Confidence Intervals: 25-159,000) human deaths, over 3.7 million (95% CIs: 1.6-10.4 million) disability-adjusted life years (DALYs) and 8.6 billion USD (95% CIs: 2.9-21.5 billion) economic losses annually. The largest component of the economic burden is due to premature death (55%), followed by direct costs of post-exposure prophylaxis (PEP, 20%) and lost income whilst seeking PEP (15.5%), with only limited costs to the veterinary sector due to dog vaccination (1.5%), and additional costs to communities from livestock losses (6%). Conclusions/Significance This study demonstrates that investment in dog vaccination, the single most effective way of reducing the disease burden, has been inadequate and that the availability and affordability of PEP needs improving. Collaborative investments by medical and veterinary sectors could dramatically reduce the current large, and unnecessary, burden of rabies on affected communities. Improved surveillance is needed to reduce uncertainty in burden estimates and to monitor the impacts of control efforts., Author Summary Rabies is a fatal viral disease largely transmitted to humans from bites by infected animals—predominantly from domestic dogs. The disease is entirely preventable through prompt administration of post-exposure prophylaxis (PEP) to bite victims and can be controlled through mass vaccination of domestic dogs. Yet, rabies is still very prevalent in developing countries, affecting populations with limited access to health care. The disease is also grossly underreported in these areas because most victims die at home. This leads to insufficient prioritization of rabies prevention in public health agendas. To address this lack of information on the impacts of rabies, in this study, we compiled available data to provide a robust estimate of the health and economic implications of dog rabies globally. The most important impacts included: loss of human lives (approximately 59,000 annually) and productivity due to premature death from rabies, and costs of obtaining PEP once an exposure has occurred. The greatest risk of developing rabies fell upon the poorest regions of the world, where domestic dog vaccination is not widely implemented and access to PEP is most limited. A greater focus on mass dog vaccination could eliminate the disease at source, reducing the need for costly PEP and preventing the large and unnecessary burden of mortality on at-risk communities.