Abstract Introduction Transthyretin amyloidosis (ATTR) is a multisystem disease caused by the deposition of fibrillar protein in organs and tissues. ATTR genotypes and phenotypes are highly heterogeneous. Purpose We designed the Transthyretin Cardiac Amyloidosis Registry in the state of São Paulo (REACT-SP), aiming to describe the demographic, genetic, clinical, and diagnostic test results and treatment of patients with ATTR. Methods We present data on physical signs and symptoms, cardiac and neurological assessments, and genetics in patients enrolled in the Transthyretin Cardiac Amyloidosis Registry in the state of São Paulo, Brazil. Results Six hundred-forty-four patients were enrolled, 505 with the variant form (ATTRv) and 139 with wild-type (ATTRwt). Sixteen different mutations were detected, the most common being Val50Met (48.3%) and V142Ile (40.8%). Overall, more than half of the patients presented cardiological involvement, and the difference in this proportion between the ATTRv and ATTRwt groups was significant (43.9 vs. 89.9%; p<0.001). The neurological phenotype also differed between ATTRv and ATTRwt (56.8 vs. 31.7%; p<0.001). The mixed phenotype was found in 25.6% of the population, without a significant difference between the forms of amyloidosis. A group of patients remained asymptomatic (10.4%), with a lower proportion of asymptomatic ATTRwt patients. The median time between the onset of symptoms and diagnosis was 1,853 (IQR 1277–2997) days, which was longer in ATTRv patients than in ATTRwt patients (p<0.001). Sinus rhythm was reported in 74.2%, atrial fibrillation in 17.0%, low voltage in 28.6%, repolarization abnormalities in 39.8%, and pseudo infarction in 27.4%. Echocardiography showed median Left Ventricular Ejection Fraction (LVEF) was 60%, Interventricular Septum (IVS) 14 mm, Posterior Wall Thickness (PWT) 13 mm, Left Atrium (LA) 41 mm, Left Ventricular Diastolic Diameter (LVDD) 45 mm, Left Ventricular Systolic Diameter (LVSD) 30 mm, basal Right Ventricular Diastolic Diameter (RVDD) 35 mm and Left Ventricle (LV) longitudinal strain 9.1%. There was some degree of LV diastolic dysfunction in 38.4%, apical sparing in 31.3%, and thrombus or masses in 1.0%. Late Gadolinium Enhancement (LGE) was absent in 29% and was subendocardial in 35.5%, transmural in 13.7%, mesocardial in 13.7%, and epicardial in 8.2%. Conclusions This study details the clinical and genetic spectrum of patients with ATTR in São Paulo, Brazil. This preliminary analysis highlights the considerable phenotypic heterogeneity of neurological and cardiac manifestations in patients with variant and wild-type ATTR.