Amyloid fibrils are associated with several disease states, but their structures have yet to be fully defined. Here we use site-directed spin labeling to explain some of the specific interactions that are formed between subunits when the protein transthyretin (TTR) assembles into amyloid fibrils, which are associated with both spontaneous and familial amyloid diseases in humans. The results suggest that fibrils are formed when a major conformational change displaces the terminal beta-strand from the edge of a beta-sheet in the native structure, exposing the penultimate strand. The newly exposed strand then allows a novel beta-sheet interaction to form between the TTR subunits. This interaction and another previously identified subunit association lead to a plausible model for the specific sequence of beta-strands in one of the indefinitely repeating beta-sheets of TTR amyloid, which is formed by a head-to-head, tail-to-tail arrangement of subunits.