People living in mining regions are exposed to numerous biological agents by several specific types of transmission mechanisms. This study is designed to describe fatal hantavirus pulmonary syndrome (HPS) cases confirmed by serology and molecular analysis, where a seroprevalence survey was conducted in the gold mining regions of the state of Mato Grosso, in the o cial Amazon region, Brazil. Two fatal cases of HPS were confirmed in a mining area in the Legal Amazon, where malaria is one of the most important public health problems. A molecular analysis detected the presence of the genome of the Castelo dos Sonhos virus. Out of the 112 blood samples analyzed, five were positive for Plasmodium infection (four P. falciparum and one P. vivax), and four were seropositive for hantavirus, showing a seroprevalence of 3.57%. One of the four miners who was seroreactive for hantavirus concomitantly had P. falciparum infection, which was confirmed by thick blood smear. This manuscript highlights the importance of considering hantavirus pulmonary syndrome as a diagnostic possibility in febrile infection associated with pulmonary manifestations in mining areas where malaria cases are often identified.