Background: In patients with poorly differentiated thyroid carcinoma, the clinical course and prognostic value of response to initial radioiodine therapy is evaluated. Methods: In 47 patients, clinical and imaging features were analyzed. Patients were stratified in no (NED), biochemical (B-ED) and structural evidence of disease (S-ED) assessed at the first diagnostic control and its impact on survival was evaluated. Further, possible risk factors for a shorter disease-specific survival rate (DSS) were analyzed. Results: In total, 17/47 patients consisted of NED, 10/47 were B-ED and 20/47 S-ED patients. At the last follow-up, 18/47 patients were NED, 2/47 patients B-ED and 27/47 patients S-ED. The median survival time was only reached for the S-ED group (median 3.9 years, 95%CI 2.8–5.1 years) and was not reached in the B-ED and NED groups. Metastases were diagnosed by a 18F-FDG-PET/CT scan in all cases and a multivariate analysis showed that the PET-positivity of metastases was the only significant predictor of DSS (p = 0.036). Conclusion: The response to initial surgery and radioiodine therapy in PDTC patients can achieve an excellent outcome and a further follow-up should be refined based on findings at the first diagnostic control. However, patients with an incomplete response and metastatic patients who become mostly radioiodine refractory show a significantly shorter survival, which makes accurate staging by 18F-FDG-PET/CT imaging crucial.