The tetrameric protein transthyretin is a transporter of retinol and thyroxine in blood, cerebrospinal fluid, and the eye, and is secreted by the liver, choroid plexus, and retinal epithelium, respectively. Systemic amyloid deposition of aggregated transthyretin causes hereditary and sporadic amyloidoses. A common treatment of patients with hereditary transthyretin amyloidosis is liver transplantation. However, this procedure, which replaces the patient's variant transthyretin with the WT protein, can fail to stop subsequent cardiac deposition, ultimately requiring heart transplantation. We recently showed that preformed amyloid fibrils present in the heart at the time of surgery can template or seed further amyloid aggregation of native transthyretin. Here we assess possible interventions to halt this seeding, using biochemical and EM assays. We found that chemical or mutational stabilization of the transthyretin tetramer does not hinder amyloid seeding. In contrast, binding of the peptide inhibitor TabFH2 to ex vivo fibrils efficiently inhibits amyloid seeding by impeding self-association of the amyloid-driving strands F and H in a tissue-independent manner. Our findings point to inhibition of amyloid seeding by peptide inhibitors as a potential therapeutic approach. This work was supported by Amyloidosis Foundation Grant 20160759 and 20170827, National Institutes of Health Grant R01-AG048120, and The Howard Hughes Medical Institute. The authors and UCLA have filed an international patent application for the TTR inhibitors (number PCT/US17/40103). D. S. E. is an advisor and equity holder of ADRx, Inc. L. S. is a consultant of ADRx, Inc. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. info:eu-repo/semantics/publishedVersion