Background: Patients with chronic Chagas disease (CD) cardiomyopathy have a high mortality. We evaluated if two-dimensional (2D) strain (ε) parameters provide independent predictors of progression to CD cardiomyopathy and all-cause mortality. Methods: A total of 408 patients with chronic CD (58.6% women; 53 ± 11 years; clinical forms: indeterminate 34.1%, cardiac 57.6%, digestive 1.2%, cardiodigestive 7.1%) were consecutively included in this single-center prospective longitudinal study. Echocardiographic evaluation included left atrial and left ventricular (LV) function on ε analyses. Primary end-point was a composite of all-cause mortality or heart transplant. Secondary end-point was CD progression defined as the occurrence of changes typical of CD in electrocardiogram, sustained ventricular tachycardia, wall motion abnormalities, or heart failure among patients with the indeterminate form at baseline. Multivariable Cox-proportional-hazards regression analyses were performed to test if 2D ε parameters were associated with the studied end-points. P values < 0.05 were considered significant. Results: The primary end-point occurred in 91 patients after a follow-up of 6.5 ± 2.7 years. CD progression occurred in 26 out of 144 patients without cardiac form at baseline (2.88 cases/100 patient-years). Peak LV circumferential (HR 1.09, 95% CI 1.01-1.18, P = .02) and radial (HR 0.97, 95% CI 0.95-0.99, P = .007) ε, and LV torsion (HR 0.51, 95% CI 0.35-0.74, P = .0004) were independent predictors of the primary end-point. Peak LV radial ε (HR 0.96, 95% CI 0.93-0.99, P = .03) was an independent predictor of CD progression. Conclusions: Therefore, 2D ε derived parameters can be useful for CD progression and mortality prediction.