Schistosoma mansoni infection is generally asymptomatic at the initial stage. However, patients left untreated can develop severe, potentially fatal clinical disease. In Brazil, S. mansoni transmission occurs in 19 states and, despite the contribution of infection to the cycle of poverty and disease, the economic impact of severe cases is unclear. Our objectives were to estimate the epidemiological burden and the costs of severe stages of S. mansoni in Brazil in 2010. We conducted an epidemiologic descriptive study and a partial economic evaluation of cost-of-illness. The study population was identified from records of notifications, hospitalizations and deaths related to S. mansoni in the respective information systems. The mortality rate for S. mansoni was 0.3 deaths per 100 000 population, which represented 1.1% of the deaths in Brazil from infectious diseases listed in Chapter I of the International Statistical Classification of Disease and Related Health Problems, 10(th) revision (ICD 10), and almost 9.0% of deaths from infection diseases in the state of Pernambuco. We calculated 6419 potential years of life lost (PYLL) to S. mansoni. The costs estimated within the public health sector totaled R$889 049.58 (US$495 016.47) and the costs of productivity losses reached R$ 35 725 332.72 (US$ 19 891 590.86) in terms of salaries lost as a result of premature death or absence from work. The cost-of-illness related to S. mansoni in Brazil was R$ 36 614 382.30 (US$ 20 386 627.12). The severe cases of S. mansoni disease still occurring in Brazil have an important epidemiologic and economic impact, representing a significant loss for society. The development of severe cases of a neglected parasitic disease that is preventable and responsive to primary healthcare intervention should be considered an expression of inequity. Our findings provide important evidence to support the strengthening of public health measures and investment to reduce poverty-related diseases in Brazil today.