The LDL receptor-associated protein (RAP) is involved in secretion of thyroglobulin (Tg) from the thyrocyte to the colloid. Disruption of the RAP gene in mice results in a reduced Tg content within the colloid, leading to subclinical hypothyroidism and histological alterations resembling early goiter. Here we studied the entire coding sequence of RAP in genomic DNA samples from 18 patients with primary hypothyroidism not due to thyroid autoimmunity or dysgenesis. The control group included 21 subjects with no evidence of thyroid alterations. Eleven different polymorphisms with amino-acid substitution and 4 different missense polymorphisms without amino-acid substitution were found in various regions of the RAP gene. Only one polymorphism in exone 7 (V311M) was observed exclusively in patients, but it had been previously reported in normal subjects as well. The remaining polymorphisms were found either both in patients and controls or only in controls and had not been previously reported. The frequency of the various polymorphisms did not differ significantly between patients and controls. Based on these findings, we conclude that alterations of the RAP gene are not a common cause of hypothyroidism, although it cannot be excluded that other, rarer alterations with a pathogenic effect exist, and that they should be investigated in a larger number of patients.