Differentiating parathyroid with pseudofollicular architecture from thyroid tissue can be challenging on intraoperative frozen sections. Birefringent calcium oxalate crystals are present in colloid of normal thyroid follicles, whereas crystals are rare in parathyroid tissue. It has been suggested that crystal identification using polarized microscopy could aid in distinguishing thyroid from parathyroid tissue on frozen sections when other ancillary studies are not available. However, the actual clinical utility of crystal detection on frozen sections has not been assessed. We reviewed all deferred or discrepant parathyroid versus thyroid intraoperative frozen section diagnoses over a 12.5-year period (17 cases). For comparison, we also reviewed 20 cases each of hypercellular parathyroid glands with pseudofollicular architecture, follicular adenomas, follicular carcinomas, follicular variant of papillary thyroid carcinomas, and nodular hyperplasias with a microfollicular pattern. These are diagnoses that could be difficult to differentiate tissue of origin (thyroid vs. parathyroid) on frozen section biopsies. Crystals were more common in thyroid (60/80) than in parathyroid (2/20) microfollicular/pseudofollicular lesions (75% vs. 10%, P<0.001). In 9 of 12 cases (75%) for which the frozen section was interpreted as or favored to be parathyroid but permanent sections showed only thyroid tissue, identification of crystals on the actual frozen section slides would have aided interpretation. This included 1 case of papillary thyroid carcinoma that was reimplanted into the patient's neck after a frozen section misdiagnosis of "parathyroid tissue" was made. We recommend examination of difficult follicular patterned parathyroid frozen sections by polarizing microscopy and deferring the diagnosis if crystals are found.