Thyroglobulin (Tg) monitoring is the biochemical standard for surveillance of recurrent differentiated thyroid cancer (DTC). Several assays are available to quantify Tg levels: immunometric assay (IMA), radioimmunoassay (RIA), and the newer liquid chromatography tandem mass spectrometry (LC-MS). It is well known that a number of entities can interfere with the accuracy of testing, and at this point in time, no one assay perfectly balances high sensitivity with low risk of interference. In this case study, we present two cases in which treatment with desiccated thyroid extract (Armour thyroid) led to a sudden elevation in Tg, which resolved when Armour thyroid was discontinued. This elevation occurred when Tg was measured with both IMA and LC-MS, which suggests direct interference from porcine Tg rather than heterophilic or thyroglobulin antibody (TgAb) interference. We suggest that patients with a history of DTC not be treated with desiccated thyroid extracts consistent with guidelines. Furthermore, more advances need to be made in the area of Tg testing to improve specificity and avoid detection of nonhuman Tg and other similar proteins.