The ultrastructure of familial amyloid polyneuropathy (FAP) amyloid fibrils was examined with high-resolution electron microscopy and immunolabeling. Sural nerve biopsies from FAP (Met 30) patients as well as control tissues were prepared for thin-section observations. Extracellular spaces in the vicinity of myelinated and unmyelinated peripheral nerves were found to be filled with amyloid fibrils as well as with deposits of an "amorphous" material. The fibril was composed of a surface layer and a core. The surface layer was made up of heparan sulfate proteoglycan and was externally associated with a loose assembly of 0.5- to 1-nn-wide filaments. The core was a microfibril-like structure in which amyloid P component was enclosed in a tight helical structure by chondroitin sulfate proteoglycan. Immunogold labeling showed that the peripheral fine filaments were composed of transthyretin. The dimensions of the transthyretin filament suggest that its basic unit is a modified monomer. The deposited amorphous material was a mixture of individual components of the fibril. These results suggest that the main body of FAP amyloid fibrils is similar to that of recently observed fibrils of experimental murine AA and hemodialysis-associated amyloid as well as of connective tissue microfibrils. The differences in the fibrils of these various types of amyloid are in the peripheral filaments which are composed of a protein specific to each type of amyoid.