Due to their unique surfactant properties, poly- and perfluorinated compounds (PFCs) have been extensively used and can be found all over the environment. Concern about their environmental fate and toxicological properties has initiated several research projects. In the present study, we investigated if PFCs can compete with thyroxine (T(4), i.e., the transport form of thyroid hormone) for binding to the human thyroid hormone transport protein transthyretin (TTR). Such competitive capacity may lead to decreased thyroid hormone levels as previously reported for animals exposed to PFCs. Twenty-four PFCs, together with 6 structurally similar natural fatty acids, were tested for binding capacity in a radioligand-binding assay. The binding potency decreased in the order: perfluorohexane sulfonate > perfluorooctane sulfonate/perfluorooctanoic acid > perfluoroheptanoic acid > sodium perfluoro-1-octanesulfinate > perfluorononanoic acid, with TTR binding potencies 12.5-50 times lower than the natural ligand T(4). Some lower molecular weight compounds with structural similarity to these PFCs were > 100 times less potent than T(4). Simple descriptors based on the two-dimensional molecular structures of the compounds were used to visualize the chemical variation and to model the structure-activity relationship for the competitive potencies of the TTR-binding compounds. The models indicated the dependence on molecular size and functional groups but demanded a more detailed description of the chemical properties and data for validation and further quantitative structure-activity relationship (QSAR) development. Competitive binding of PFCs to TTR, as observed for human TTR in the present study, may explain altered thyroid hormone levels described for PFC-exposed rats and monkeys. Median human blood levels of the most potent TTR-binding PFCs are one to two orders of magnitude lower than concentration at 50% inhibition (IC(50)) values determined in the present study. In addition, this study contributes to the understanding of the bioaccumulation of PFCs in man and possibly in other wildlife species.