Senile systemic amyloidosis (SSA) is a prevalent disease affecting the elderly and results from the pathologic deposition, predominantly in the heart, of unmutated (wild-type) transthyretin (TTR) molecules. This disorder differs from the familial TTR-associated amyloidoses that generally occur in a younger population and involves peripheral nerves but, notably, the deposits contain mutated (variant) forms of the amyloidogenic precursor protein. To gain further insight into the clinicopathologic features and pathogenesis of SSA, we have reviewed the post-mortem findings of 33 Swedish individuals (27 men, 6 women) who had pronounced cardiac amyloid disease. Additionally, in all cases there were amyloid deposits within the lungs. Seven of the patients were uremic, possibly due to fibrillar deposits in the renal medullary papilla. In contrast to other systemic amyloidoses, none of the 33 had more than minute congophilic material in the renal cortex, liver, or spleen. We have also analyzed the chemical composition of fibrils extracted from myocardium and have found that the protein consisted mainly of C-terminal fragments of TTR starting at positions 46, 49, and 52. Furthermore, we identified through antigenic mapping, an epitope present on the H strand of fibrillar, but not normal, plasma TTR molecules indicating that this strand is exposed in fibrils. We suggest that ATTR fibrils may develop both from full-length TTR and from C-terminal TTR fragments and that the N-terminal part is not necessary for the fibril integrity.