Hypertension is the most common cause of left ventricular (LV) hypertrophy. However, multiple causes can lead to LV hypertrophy, each of which has different histological and mechanical properties. To assess the value of a novel speckle-tracking echocardiographic measurement of myocardial strain and strain rate in defining the mechanical properties of LV hypertrophy, 20 patients with asymmetric hypertrophic cardiomyopathy, 24 patients with secondary LV hypertrophy, 12 patients with biopsy-proved confirmed cardiac amyloidosis, and 22 age-matched healthy asymptomatic volunteers were studied. Patients with amyloidosis had severe diastolic dysfunction, and myocardial deformation was significantly decreased. The new technique allowed cardiac amyloid to be easily differentiated from the other categories. In patients with hypertrophic cardiomyopathy, there was segmental myocardium dysfunction as assessed by strain imaging. LV global systolic velocity and radial displacement were higher, and abnormal relaxation was more frequent, in the group with secondary LV hypertrophy than in normal controls. In conclusion, the observations from strain parameters derived from speckle tracking were consistent with the known underlying pathology of each condition, which speaks to the value of strain imaging. Cardiac amyloid profoundly alters all strain parameters, and analysis of these parameters could aid in the diagnosis.