Macrophages/histiocytes are commonly seen in fine-needle aspiration biopsy (FNAB) specimens of thyroid nodules with varying degrees of cystic change. In some cases the histiocytic component of a cystic thyroid nodule can occur as large tissue fragments with marked nuclear atypia, including elongated nuclei with chromatin clearing, nuclear grooves, and membrane thickening. These nuclear changes mimic cytologic features of papillary thyroid carcinoma (PTC), thus leading to diagnostic difficulty in interpretation of FNAB specimens of benign cystic thyroid nodules. We evaluated ethanol-fixed Papanicolaou-stained smears of 273 cases of FNAB thyroid specimens from goitrous nodules with cystic change. Twenty cases were selected due to the presence of large aggregates of histiocytic cells with the above-mentioned nuclear atypia. An immunostain for histiocytic cells using CD68 was performed on alcohol-fixed slides. Histiocytic cells in tissue fragments with nuclear atypia mimicking PTC nuclei showed strong cytoplasmic staining for CD68; thyroid follicular cells stained negative for CD68. We conclude that histiocytic cells in cystic goitrous nodules can show nuclear features, which appear similar to PTC nuclei. Immunostaining for CD68 may be of value in differentiating between benign cystic thyroid nodules with histiocytic aggregates that mimic cytologic features of papillary carcinoma, and PTC with cystic change.