Plasma cell granuloma of the thyroid is an uncommon lesion; only 6 cases have been reported in the English literature to date. All reported cases occurred in women, mostly after the age of 50 years. We report a case of plasma cell granuloma of the thyroid in a 46-year-old woman with a 20-year history of euthyroid goiter and a positive family history of goiter in 3 close relatives. The lesion was composed of sheets of plasma cells involving the entire parenchyma that histologically resembled plasmacytoma. Plasmacytoma was excluded by demonstration of polyclonal kappa/lambda light chain immunostaining and by lack of evidence of clonal bands by polymerase chain reaction for immunoglobulin heavy-chain gene rearrangement. Similarly, the predominant histologic pattern in all previously reported cases is that of marked plasma cell infiltration. A family history of thyroid disease (goiter, thyroiditis) was associated with diffuse involvement of the thyroid. Prognosis after surgery is excellent, and to our knowledge no cases of malignant transformation or recurrence have been described.