The thyroids of two brothers aged 13 and 15 with congenital goitre, butanolinsoluble iodine in blood and which had pronounced decrease of immunoreactive thyroglobulin content in the thyroid were studied. Two types of thyroglobulin were identified. The first amounted to only about 200-300 mug/g wet tissue and was fully immunoreactive with anti normal human thyroglobulin antiserum (iTG-G). It was purified by affinity chromatography. The other was mainly associated with intracytoplasmic membranes, amounted to about 8 mg/g wet tissue and was only partially immunoreactive (piTG-G). Both had abnormal amino acid compositions but only iTG-G showed a decreased carbohydrate content. Surprisingly, piTG-G showed a normal iodination level (0-5%) and a normal iodoamino acid composition. Immunochemical studies performed on slices or cell-free fractions incubated in the presence of labelled amino acids and/or monosaccharides showed that: (1) thyroglobulin peptide chains were being synthesized and almost normally discharged into the cisternae of the rough endoplasmic reticulum; (2) incorporation of sugars into iTG-G was decreased; (3) sialyl- and galactosyltransferase activities were normal and the enzymes normally located, and (4) albumin which is present in the thyroid as the iodinated protein was probably not synthesized by the goitrous tissues. Two major abnormalities were detected by light and electron microscopy: absence or pronounced scarcity of colloid in the follicular lumina and overdistended endoplasmic reticulum cisternae. These observations are compatible with a defect in TG transport from the cell into the lumen as the cause of the goitre. Whether defective thyroglobulin export is basically related to abnormality of the protein structure or to another cause is discussed.