Background Six to 20% of thyroid cancer (TC) patients develop distant metastases, and one third become radioiodine refractory (RAIR). Available targeted therapies increase progression free survival but are associated with toxicities. This study aims to characterize clinical, pathological and molecular profiles of patients with RAIR TC.Data of TC patients seen 2013-2017 at two tertiary care centers were retrospectively analyzed. Patients were considered RAIR according to ATA guidelines (5). The control cohort was gender- and age-matched and had either regression or stable disease (by RECIST) on follow up at least 3 years after initial therapy. Molecular profiles on a subset of RAIR patients were reviewed.Compared to 22 matched controls, 54 RAIR patients had average age 57 yr (SD=13), 56% were male ; average tumor size was 4 cm (SD=2.5); tumors were multifocal in 54%, with involved surgical margins in 42%, focal invasion in 79%, and extrathyroid extension (ETE) in 61%. Sixty six percent had distant metastases initially with metastases to lung in 85%, bone in 56%, both sites in 43%, brain in 9% and liver in 4%. There were no statistically significant differences between RAIR and controls in tumor size, focal invasion, ETE and histology. The RAIR group had higher cumulative RAI dose and number of therapies vs. control (518 vs 302 mCi, p=0.002 and 2.2 vs 1.3 treatments, p=0.001). Overall, patients >46 years had 4.5 times higher odds ratio (OR) of being RAIR ; white race was associated with a reduced OR of RAIR disease (OR 0.33, p=0.079). Molecular profiling data in the RAIR subgroup indicated that 50% of patients harbored mutations in the RAS/RAF pathway (11/22). Among 19 patients with a more extensive molecular panel, median tumor mutational burden was 5 mb (range: 3-16) and 26% (5/19) exhibited strong PD-L1 positivity.Among patients with metastatic DTC, patients with RAIR have similar histopathological and clinical characteristics as patients with RAI avid cancer. The risk of having RAIR TC is increased at age ≥ 46 and reduced in Caucasians. Thyroid cancers that are RAIR may have a distinct mutational landscape.