ABSTRACT Yellow fever virus (YFV) is widely distributed in the tropics of South America and Africa, being responsible for massive yellow fever outbreaks causing deaths of thousands of people in recent years. YF usually occurs in remote areas of Africa and the Americas where patients have little or no access to advanced medical care and laboratory tests; therefore, much of what we know about YF in humans is very limited including poorly understood epidemiology, pathogenesis, therapeutic approaches, and host/virological determinants of disease during different phases of infection. In December 2016, a massive sylvatic YF outbreak (2,155 human cases) took place in Southeast Brazil, with 46% of total cases (n=1,002) and 37% of deaths (n=340) occuring in Minas Gerais state. From 2016 to 2018, a total of 299 confirmed YF cases were admitted at Eduardo de Menezes Hospital, in Belo Horizonte, Minas Gerais. Our group has maintained a database containing epidemiological and clinical data with long-term follow up from those patients, as well a biological bank of clinical samples that can be probed to redefine the clinical course and pathogenesis of this important pathogen. Our unique well-characterized cohorts include: (i) patients who evolved to death; (ii) patients who recovered; (iii) patients who recovered and developed a novel clinical syndrome named late hepatitis-like syndrome after yellow fever (LHep-YF); and (iv) patients who received off-label treatment with sofosbuvir. Here we propose to (i) redefine the clinical course of YF and determine the social, demographic, and co-morbid risk factors for severe presentations of disease, including development of LHep-YF, (ii) investigate the viral and immunologic pathogenesis of YF throughout the continuum of disease and (iii) predict YF prognosis by identifying virological and immunological biomarkers associated with severe disease and assessing the effects of potential treatments. Our experienced research team will take an interdisciplinary approach that integrates basic and applied virology, immunology, epidemiology, and clinical infectious disease to fill important gaps on epidemiology, clinical disease, pathophysiology, and biology of YFV. The recent YFV outbreaks in Southeast Brazil create an unprecedented opportunity to analyze our unique bank of data and well-preserved samples from hundreds of hospitalized YF patients. This information will be crucial for the establishment of protocols and more applied studies to prevent morbidity and mortality from this important pathogen.