Introduction: The 2015 American Thyroid Association (ATA) guidelines recommend response to therapy (RTT) assessment 1-2 years after initial treatment in differentiated thyroid cancer (DTC) patients to guide thyrotropin (TSH) goals and long-term follow-up. We hypothesized that data collected during the first 2 years of follow-up may be sufficient to determine RTT without thyroglobulin (Tg) stimulation.Materials and Methods: Patients treated with total thyroidectomy and radioiodine for intermediate-risk DTC, followed for >2 years, and had sufficient follow-up data were included. Data on Tg, ultrasound, scans, and long-term outcomes were collected.Results: One-hundred twenty patients met inclusion criteria, with 68% women and mean age 55 +/- 15 years. Intermediate risk was due to lymph-node involvement (72%), extrathyroidal extension (51%), vascular invasion (12%), and high-risk histology (9%). At the end of follow-up of 7 +/- 4 years, 26% had persistent disease (14% biochemical, 12% structural). According to the ATA RTT system (using stimulated-Tg), 56% had excellent RTT, of whom only 2% had disease at the end of follow-up. In the "nonstimulated" system (which includes basal Tg, post-I-131 therapy whole-body scan (TxWBS) for assessment of residual lymph-node metastases after surgery, and structural imaging studies), 57% had excellent response, of whom none had disease at the end of follow-up. Only eight patients (7%) were classified differently due to recombinant human thyrotropin stimulation (as either excellent or indeterminate response), with no difference in predictive value, with a receiver-operator characteristic area under the curve of 0.903 with Tg-stimulation and of 0.918 without.Conclusions: In patients with no evidence of disease during the first 2 years of follow-up, the addition of stimulated-Tg adds little prognostic information. We suggest the use of excellent RTT based on basal Tg together with TxWBS and structural imaging studies.