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Introduction: There are few contemporary prospective cohorts of Trypanosoma cruzi ( T.cruzi )-infected individuals. This study aimed to determine the incidence of new-onset cardiomyopathy and death attributable to T. cruzi infection. Methods: We enrolled 1088 individuals: 499 T. cruzi -seropositive blood donors identified in routine donor screening, 488 age- and sex-matched T. cruzi - seronegative blood donors, and 101 patients with established Chagas cardiomyopathy recruited from a tertiary center. Subjects underwent cardiovascular evaluation with ECG and echocardiogram at the baseline (2008-2010) and follow-up (2018-2019) visits. Cardiomyopathy was diagnosed based on ECG and echocardiographic findings at baseline and follow-up. Vital status was determined by linkage with the national Brazilian mortality system. Results: Mortality was 80.9 deaths/1000 person-years (py) in established cardiomyopathy and 15.1 deaths/1000py in T. cruzi -seropositive donors with cardiomyopathy at baseline. The mortality rate among T. cruzi -seropositive blood donors without cardiomyopathy at baseline and T. cruzi -seronegative controls was similar, with mortality rates of 3.67 and 3.62 events/1000 py, respectively. In T. cruzi -seropositive donors, age (hazard ratio [HR] = 1.05 per year), anti-T.cruzi antibody level (HR = 1.40 per unit increase in serology assay signal/cut off) and the presence of cardiomyopathy at baseline (HR = 3.01) were independent predictors of mortality. The incidence of new-onset cardiomyopathy in T. cruzi -seropositive donors was 13.8 events/1000 py (95% CI 9.5-19.6) compared with 4.6 events/1000 py (95% CI 2.3-8.3) in controls, with an absolute incidence difference attributable to T. cruzi infection of 9.2 (95% CI 3.6 - 15.0) events/1000py. T. cruzi antibody level at baseline was the main independent predictor of subsequent new-onset cardiomyopathy with an adjusted odds ratio of 1.37 (95% CI 1.07-1.76) per unit increase in antibody level. Conclusions: We present a comprehensive description of the natural history of T. cruzi infection in a contemporary patient population. The results highlight the central importance of total anti- T. cruzi antibody titer as a marker of Chagas disease activity and risk of progression.