AbstractObjectiveExposure to therapeutic radioactive iodine (RAI) is associated with an increased relative risk of myeloid malignancies. Clonal hematopoiesis (CH) is a precursor state that can be detected in blood of healthy individuals decades before overt development of leukemia. We prospective studied the effects of RAI on CH.DesignProspective cohort study.Patients and MeasurementsWe examined the effect of RAI on CH in 20 patients exposed to RAI for thyroid carcinoma and 20 age‐matched unexposed controls. CH status was determined at baseline, 6, 12, 18 and 24 months. We also examined the effect of CH on structural progression of disease.ResultsNo CH mutations were observed in the patient population that were not present at baseline. Using a variant allelic fraction (VAF) of 2% to define CH, 6/20 older patients (55−80 years old) had CH compared to 2/20 younger patients (20−40 years old) (p = 0.11). Six patients exposed to RAI had CH compared to two patients not exposed to RAI (30% vs. 10%, p = 0.11). There was no significant difference in CH VAF increase in patients treated with RAI compared to untreated age‐matched controls (3.8% vs. 1.2%, p = 0.2). CH was significantly associated with somatic BRAFV600E mutations and with worse progression‐free survival in the overall cohort as well as among BRAFV600E‐mutant tumors.ConclusionsThere was no increase in CH in patients treated with RAI over a 2‐year follow‐up period. Larger studies with longer follow‐up periods are needed to investigate the association between RAI and clonal dynamics. The presence of CH is associated with worse structural progression in both BRAFV600E‐mutant and wild‐type thyroid cancers.