Thyroid hyperplasia is a physiologic response of follicular epithelium to hormonal changes that result in disturbances in the feedback mechanism of thyrotropin-releasing hormone and thyroid-stimulating hormone. The most common manifestation of this process is the so-called sporadic goiter (diffuse or nodular hyperplasia), a condition that may be associated with a variety of stimuli. Some of the histologic changes that can be observed in hyperplasia of the thyroid can sometimes lead to an incorrect diagnosis of malignancy. We studied 300 consecutive cases of hyperplasia of the thyroid to evaluate morphologic features that could potentially be mistaken for neoplastic conditions. Florid papillary hyperplasia of follicular epithelium was observed in 13% of cases, in several instances closely resembling the papillary structures of papillary thyroid carcinoma. Foci displaying nuclear clearing closely resembling "Orphan-Annie" nuclei were present in 15% of cases. Nuclear grooves and pseudonuclear inclusions were also identified focally in 8% of cases. Cytologic atypia was observed in 7% of cases, including nuclear enlargement, multinucleation, and nuclear pleomorphism with prominent nucleoli. Mitoses were observed in 6% of cases and averaged 1 to 2 per 20 high-power fields. This finding was usually seen in the more cellular areas in cases characterized by a solid, microfollicular pattern of growth. Psammoma bodies were observed focally in 4 cases (1.3%). Infiltration of adjacent skeletal muscle by benign hyperplastic follicles was seen in 3 cases (1%). Another unexpected finding in 2 cases was the identification of small clusters of normal thyroid follicles within the sinuses of lymph nodes located adjacent to the gland (>1%). The present study confirms that thyroid hyperplasia can sometimes display features that may be confused for a malignant neoplastic process. Awareness of such features and their recognition are of importance to avoid a misdiagnosis of malignancy.