Amyloid fibrils were isolated from the myocardium of two patients with familial amyloid polyneuropathy. The solubilized amyloid fibril whole protein shared immunologic determinants with normal human serum prealbumin (transthyretin), but revealed subtle differences on immunoelectrophoresis and radial immunodiffusion. On sodium dodecyl sulfate-polyacrylamide gel electrophoresis, amyloid fibril whole protein was resolved into numerous bands that reacted with antitransthyretin on immunoblots. The whole protein also contained peptide fragments of fibronectin, but was devoid of amyloid P protein. An antiserum raised against the whole protein was suitable for immunocytochemistry of amyloid in paraffin sections. In contrast, commercial antitransthyretin, raised against the intact tetrameric protein failed to react with tissue amyloid. Immunochemical and immunocytochemical results support the concept that familial amyloid polyneuropathy with cardiomyopathy is due to infiltration of susceptible tissues by an anomalous transthyretin.