Familial amyloidotic polyneuropathy (FAP) is characterized by extracellular deposition of amyloid fibrils caused by a point mutation in the transthyretin (TTR) gene. Despite data from a number of in vitro studies of TTR amyloidogenesis, many questions, including where and how these fibrils form in vivo and what is the impact of amyloid deposition on tissues, remain unanswered. Here, we analysed the relationship between amyloid fibril formation and micro-environmental changes by using autopsy cardiac tissues from 11 patients with FAP and a smooth muscle cell line. Ultrastructural studies of cardiomyocytes and vascular smooth muscle cells showed that amyloid fibrils formed first at the basement membrane and that amorphous non-fibrillar TTR deposits and premature fibrils predominated during the early stage of amyloid deposition. Immunohistochemical analyses revealed that expression of major components of the basement membrane, such as collagen IV, laminin, and fibronectin, increased in parallel with the accumulation of TTR amyloid fibrils. In vitro studies with a vascular smooth muscle cell line revealed that synthetic TTR aggregates increased expression of these basement membrane components. Serum levels of collagen IV in FAP patients were significantly higher than those in healthy controls. Our data thus indicate that TTR amyloid fibrils formed first at the basement membrane and that expression of basement membrane components that was induced by amyloid deposition contributed to further amyloid deposition. This chain reaction may have important implications for FAP pathogenesis.