Background Chagas disease (CD) presents an ominous prognosis. The predictive value of biomarkers and new echocardiogram parameters in adjusted models have not been well studied. Methods and Results There were 361 patients with chronic CD (57.6% men, 61±11 years of age, clinical forms: indeterminate 27.1%, cardiac 56.6%, digestive 3.6%, cardiodigestive 12.7%) included in this single-center, observational, prospective longitudinal study. Echocardiographic evaluation included strain analyses of left atrial, left ventricular (LV), and right ventricular and 3-dimensional analyses of left atrial and LV volumes. Biomarkers included cardiac troponin I, brain natriuretic peptide, transforming growth factor β1, tumor necrosis factor, matrix metalloproteinases, and polymerase chain reaction. The studied end point was a composite of CD-related mortality, heart transplant, hospital admission due to worsening heart failure, or new cardiac device insertion. Event-free survival was analyzed by multivariable regression analyses adjusted for competing risks. values <0.05 were considered significant. The composite event occurred in 79 patients after 4.9±2.0 years follow-up. LV end-diastolic volume (hazard ratio [HR], 1.01 [95% CI, 1.00-1.02]; =0.02), peak negative global atrial strain (HR, 1.08 [95% CI, 1.00-1.17]; =0.04), LV global circumferential strain (HR, 1.12 [95% CI, 1.04-1.21]; =0.003), LV torsion (HR, 0.55 [95% CI, 0.35-0.81]; =0.003), brain natriuretic peptide (HR, 2.03 [95% CI, 1.23-3.34]; =0.005), and positive polymerase chain reaction (HR, 1.80 [95% CI, 1.12-2.91]; =0.01) were end point predictors independent from age, sex, 2-dimensional echocardiographic indexes, hypertension, previous cardiac device, and CD cardiac form. Conclusions Two-dimensional strain- and 3-dimensional-derived parameters, brain natriuretic peptide, and positive polymerase chain reaction can be useful for prediction of CD cardiovascular events.