Introduction: Differentiated thyroid cancers such as papillary and follicular thyroid cancer make up more than 90% of all thyroid cancers. The presence of thyroglobulin autoantibodies makes interpretation of the thyroglobulin level unreliable, as it could be falsely low or falsely high. Studies have shown that rising thyroglobulin antibody levels, could be used to monitor for disease recurrence in patients with negative thyroglobulin and imaging studies. However, there are challenges in detecting recurrence in patients with normal thyroglobulin level and thyroid imaging studies, who are on lifelong immunoglobulin therapy and who have increasing thyroglobulin antibody levels.Clinical case: A 63 yr old female was found to have an incidental left thyroid nodule at age 48yrs from a carotid ultrasound. She underwent US guided FNA of the thyroid nodule and was found to have papillary thyroid cancer. She had total thyroidectomy a month later, with removal of a 1.4cm primary, with no evidence of extrathyroidal extension, clear margins and no evidence of lymphovascular invasion – Stage T1bN0M0. There was left level 6 neck dissection with no carcinoma identified in the 2 lymph nodes removed. She received 105.3 mCi radioactive iodine (RAI) and whole body thyroid scan done 7 days later revealed, increased uptake involving the thyroid bed likely residual thyroid tissue. Activity was noted inferolateral to the right thyroid bed which most likely represents a lymph node. There was no evidence of distant metastasis.She was commenced on levothyroxine post operatively. Her other past medical history is significant for idiopathic urticaria and angioedema, immune deficiency disorder with low IgG and IgM and asthma. She was commenced on monthly IV immunoglobulins 5yrs post RAI therapy, due to recurrent sinusitis, rhinitis and chronic diarrhea. She was later transitioned to weekly SQ immune globulin – Hizentra which she is on till date.Over the past 15 years, serial neck ultrasounds post radioiodine ablation have been negative for recurrence. Her TSH ranged 14.91 to 0.04 (ref 0.27-4.2 uiu/ml) and thyroglobulin (Tg) titer remains <0.1 (ref <0.1). Her thyroglobulin antibody titers have trended up from <0.2 (ref <2.0) 5yrs post RAI therapy to 49 (ref <4 iu/ml)) on her most recent test this year. She is currently undergoing further work up to rule out recurrence of her cancer. In our review of the literature we found one report that showed use of Liquid Chromatography–Mass Spectrometry (LC-MS) was able to differentiate thyroid cancer recurrence in an individual with positive antithyroglobulin antibody receiving immunoglobulin therapy.Conclusion: In patients with negative Tg levels, but elevated thyroglobulin antibody while receiving immune globulin therapy, thyroglobulin antibody levels may not be a reliable indicator of thyroid cancer recurrence. Measurement of Tg levels using a LC-MS may provide some clarity.