Objective To investigate the relationship between the initial change of thyroglobulin (Tg) and clinical outcome in differentiated thyroid carcinoma (DTC) patients with pulmonary metastases after 131I treatment. Methods A total of 69 DTC patients with pulmonary metastases from January 2010 to December 2015 were retrospectively analyzed. Patients were divided into 3 groups according to the variation of Tg: groupⅠ(Tg declined≥ 50%), groupⅡ(Tg declined＜50% or Tg increased＜10%), and group Ⅲ (Tg increased ≥10% ). The follow-up time was (49.2 ± 9.3) months. Clinical outcomes were divided into remission, stable disease and progressive disease according to the serum test and imaging results. Results The percentage of group Ⅰ, Ⅱ, Ⅲ patients was 44.9% (31/69), 40.6% (28/69), and 14.5% (10/69) respectively. Results of follow-up showed 19.4% (6/31) patients achieved remission and 80.6% (25/31) had stable disease in groupⅠ. There were 10.7% (3/28) patients with remission, 60.7% (17/28) with stable disease and 28.6% (8/28) with progression disease in groupⅡ. All patients showed progressive disease in groupⅢ. The clinical outcome was related to the variation of Tg after 131I treatment (P＜0.01). Conclusions Initial Tg after 131I treatment could be a predictor to the outcome of patients. The increased Tg level indicates a high possibility of 131I refractory disease.