Purpose To introduce a biomarker-based dosimetry method for radioactive iodine 131I therapy (RAI) of metastatic differentiated thyroid cancer (mDTC), adapted to the underlying heterogeneity of lesions’ radiation-absorbed dose (RAD) in cGy, and permitting 1) estimates of RAD/lesion with known precision and 2) optimization of patient-specific administered amount of radioactive iodine (131I) in MBq. Methods Patients referred for RAI therapy of mDTC were enrolled in institutionally approved protocols. A total of 208 mDTC lesions (in 21 patients) with SUV > 1 underwent quantitative PET scans at 24, 48, 72, and 120 hours post-administration of 222 MBq of theranostic NaI-124I to determine the individual lesion RAD (in cGy) based on MIRD 2020 guidance. Using a general estimating equation, a prediction curve for biomarker development was generated in the form of a best-fit regression line and 95% prediction interval, correlating individual predicted lesion RAD metrics, with candidate biomarkers (“predictors”) such as SUV and activity in microcurie per gram, from a single imaging timepoint. Results In the 169 lesions (in 15 patients) that received 131I therapy, individual lesion cGy varied over 3 logs with a median of 22,000 cGy, confirming that heterogeneity of lesion RAD was profound. Initial findings from the prediction curve on all 208 lesions confirmed that 48h SUV was the best predictor of lesion RAD and permitted calculation of the 131I required (in MBq) to achieve a lesional threshold dose for response (2,000 cGy) in more than 95% of lesions. Conclusions Based on MIRD lesion RAD estimates and regression statistics, we propose and report initial feasibility for an 124I-PET-based dosimetry biomarker for RAI in patients with mDTC. This approach enables clinicians to select personalized (precision) therapeutic administration of radioactivity (MBq) to achieve a desired target lesion-absorbed doses (cGy) for > 95% of all lesions using a single 48-hour measurement 124I-PET image. NCT04462471, Registered July 8, 2020. NCT03647358, Registered Aug 27, 2018.