The diagnosis of cardiac amyloidosis (CA) is challenging owing to vague symptomatology and non-specific echocardiographic findings. To describe regional patterns in longitudinal strain (LS) using two-dimensional speckle-tracking echocardiography in CA and to test the hypothesis that regional differences would help differentiate CA from other causes of increased left ventricular (LV) wall thickness. 55 consecutive patients with CA were compared with 30 control patients with LV hypertrophy (n=15 with hypertrophic cardiomyopathy, n=15 with aortic stenosis). A relative apical LS of 1.0, defined using the equation (average apical LS/(average basal LS + mid-LS)), was sensitive (93%) and specific (82%) in differentiating CA from controls (area under the curve 0.94). In a logistic regression multivariate analysis, relative apical LS was the only parameter predictive of CA (p=0.004). CA is characterised by regional variations in LS from base to apex. A relative 'apical sparing' pattern of LS is an easily recognisable, accurate and reproducible method of differentiating CA from other causes of LV hypertrophy.