The World Health Organization estimates that 50–100 million dengue infections occur annually. However, estimates based on cartographic modeling approaches suggest that up to 390 million dengue infections annually. Dengue has become an increasing public health concern in the Americas. A substantial number of cases in the Americas are reported in Brazil. There is a need for an updated evaluation of the economic impact of dengue in Brazil so as to allow decision/policy makers to make informed decisions on resource allocation and strategic planning. We estimated the economic burden of dengue in four regions. National cost estimates were based on the number of cases reported in Sistema de Informacao de Agravos de Notificacao (SINAN). Overall, 2,035 (91.5%) dengue cases were recruited to our study. More than 2 million suspected dengue cases and 569 deaths were reported in SINAN from September 2012 to August 2013. The annual national economic burden was US$ 164 million from the public payer perspective, but may be as high as US$ 447 million (adjusting for underreporting). From the societal perspective, the economic burden was US$ 468 million, but may be as high as US$ 1,212 million. The economic burden associated with dengue in Brazil is substantial.