This study delineates tumor characteristics which predispose serum thyroglobulin (TG) to be undetectable in patients in spite of persistent or recurrent differentiated thyroid cancer. Three hundred seventy four thyroid carcinoma patients with completed thyroid ablation were investigated by means of conventional diagnostic procedures (131 iodine total-body scan, x-ray, TG determination) and, in addition, with high-resolution sonographic study of the neck. Sensitivity of TG for the detection of metastases amounted to 83% under TSH stimulation and 50% under thyroxine (T4) treatment. Specificity proved to be 95% under TSH stimulation and 99% under T4 treatment. Common features of the tumors associated with false-negative TG determinations (n = 16) were papillary histologic characteristics, manifestation in lymph nodes of the neck or mediastinum, and small size. It is therefore necessary for the early detection of persistent or recurrent papillary cancer metastases to perform in addition to 131 iodine scans high-resolution sonography of the neck in combination with the determination of TG serum concentrations under endogenous TSH stimulation.