OBJECTIVES: This study evaluated whether 2-dimensional speckle-tracking echocardiography (2D-STE) has incremental value for prognosis over traditional clinical, echocardiographic, and serological markers-with main focus on the current prognostic staging system-in light-chain (AL) amyloidosis patients with preserved left ventricular ejection fraction. BACKGROUND: Cardiac amyloidosis (CA) is the major determinant of outcome in AL amyloidosis. The current prognostic staging system is based primarily on serum levels of cardiac troponin T (cTnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and free light chain differential (FLC-diff). METHODS: Consecutive patients with biopsy-proven AL amyloidosis and left ventricular ejection fraction ≥55% were divided into group 1 with CA (n = 63) and group 2 without CA (n = 87). Global longitudinal strain (GLS) by 2D-STE was performed with Vivid E9 (GE Healthcare Co., Milwaukee, Wisconsin) and syngo Velocity Vector Imaging (VVI) software (Siemens Medical Solutions USA, Inc., Malvern, Pennsylvania) (GLSGE and GLSVVI, respectively). RESULTS: Thirty-two deaths (51%) occurred in group 1 and 13 (15%) in group 2 (p ≤ 0.001). Group 1 had thicker walls, lower early diastolic tissue Doppler velocity at septal mitral annulus, and greater left ventricular mass, left atrial volume, glomerular filtration rate, FLC-diff, cTnT, and NT-proBNP (p < 0.001). For the entire cohort, GLSGE ≥ -14.81, GLSVVI ≥-15.02, cTnT, NT-proBNP, FLC-diff, age, left ventricular wall thickness, early diastolic tissue Doppler velocity at septal mitral annulus, diastolic dysfunction grade, glomerular filtration rate, deceleration time, and left atrial volume were univariate predictors of death. In a multivariate Cox model, GLSGE ≥-14.81 (hazard ratio [HR]: 2.68; 95% confidence interval [CI]: 1.07 to 7.13; p = 0.03), FLC-diff, NT-proBNP, and age were independent predictors of survival. There was also a strong trend for GLSVVI ≥-15.02 (HR: 2.44; 95% CI: 0.98 to 6.33; p = 0.055). Using a nested logistic regression model, GLSGE (p = 0.03) and GLSVVI (p = 0.05) provided incremental prognostic value over cTnT, NT-proBNP, and FLC-diff. For survival analysis limited to group 2 (non-CA), GLSGE and GLSVVI both predicted all-cause mortality (GLSGE HR: 1.23; 95% CI: 1.03 to 1.47 [p = 0.02]; GLSVVI HR: 1.22; 95% CI: 1.01 to 1.49 [p = 0.04], respectively). CONCLUSIONS: 2D-STE predicted outcome and provided incremental prognostic information over the current prognostic staging system, especially in the group without CA.