Background: Increased interventricular septal (IVS) thickness by echocardiography with low-voltage on electrocardiogram (ECG) is commonly used as an indicator of amyloid heart disease. We have observed a subset of patients with amyloid who have heart failure and normal IVS thickness. Methods: All patients with amyloidosis and left ventricular ejection fraction (LVEF) # 40% between 1983 and 2010 were analyzed to identify those with normal BMI-weighted IVS thickness. Patients with a history of coronary artery disease were excluded. Results: There were 255 patients identified of which 19 patients (M5 15, F5 4) had normal IVS thickness. The mean age of this group was 64.7 6 10.3 years. Eighteen had primary systemic amyloidosis and one had hereditary amyloidosis. All 19 patients had amyloidosis proven by biopsy. Edema, dyspnea, and weight loss were the most common presenting symptoms with mean duration from onset to presentation being 5.2 6 3.1, 6.5 6 5.5, and 7.9 6 7.3 months respectively. Common ECG findings despite normal IVS thickness included low-voltage (26%) and a pseudoinfarct pattern (37%). Mean IVS thickness was 11.1 mm 6 1.6, LV end diastolic volume 50.7 mm 6 7.1, and LV mass index was 114g 6 23.8 amongst this cohort. Grade 3 or 4 diastolic dysfunction was observed in 5 of 19 patients. Nine patients had a thickened mitral valve and of these 2 had a thickened tricuspid valve. Median survival from initial tissue diagnosis amongst the normal IVS thickness cohort (group 1) was 4.5 months as compared to 3.5 months in age and gender matched controls with increased IVS thickness and LVEF # 40% (group 2, n557). Mortality in both groups is high with 81% of patients in group 1 and 79% of patients in group 2 dying within one year of onset of symptoms. Conclusion: A subset of patients with amyloidosis and cardiomyopathy present with normal IVS wall thickness. This group accounts for 7 % of patients with amyloidosis and LVEF#40%. Albeit an unusual presentation, amyloidosis must be considered in the differential diagnosis of patients with cardiomyopathy with reduced EF and normal IVS thickness. The prognosis of these patients is as poor as those with increased IVS thickness.