PURPOSE: This study evaluated the impact of (124)I-positron emission tomography (PET) dosimetry on post-primary surgery therapy in radioiodine-naïve patients with advanced differentiated thyroid cancer (DTC). PATIENTS, MATERIAL, METHODS: In each of 28 thyroidectomized patients with high-risk DTC (one or more of pT4, pN1 or pM1), we gave 23-50 MBq of (124)I as an oral capsule and performed PET dosimetry to calculate the individualized therapeutic (131)I activity that would, insofar as possible, achieve a radioiodine dose >or=100 Gy to all metastases without exceeding 2 Gy to the blood (a surrogate for bone marrow toxicity). We thus determined the absorbed lesion dose per GBq of administered 131I activity (LDpA) based on serial PET (4, 24, 48, 72 and 96 h after oral 124I intake) and PET/computed tomography (25 h after (124)I intake) and the critical blood activity (CBA) based on blood and whole-body radiation counting (2, 4, 24, 48, 72, 96 h after 124I intake). We compared the dosimetry-based interventions with our standard empirical protocol. RESULTS: 25 patients had a total of 126 iodine-positive metastases. 18 (72%) of the 25 had solely iodine-avid metastases, while seven (28%) had both iodine-avid and -non-avid metastases. In two patients (8%), none of the iodine-avid metastases could have been practically treated with a sufficient radiation dose. Relative to the empirical protocol, (124)I-PET dosimetry findings changed management in 7 (25%) patients, e.g. allowing application of activities >11 GBq (131)I. Further changes included implementation of hematological back-up in a patient found to be at risk of life-threatening marrow toxicity, and early multimodal therapy in 9 (32%) patients. CONCLUSION: 124I-PET dosimetry is a useful routine procedure in advanced DTC and may allow safer or more effective radioiodine activities and earlier multimodal interventions than do standard empirical protocols.