False negative thyroid nodules are those with a benign diagnosis on fine needle aspiration biopsy but a malignant diagnosis on final surgical pathology following resection. Many studies have attempted to correlate thyroid nodule size with false negative rates, specifically in large nodules (>3 cm or >4 cm) compared to those of smaller size. This chapter analyzes 35 published articles (1 Jan 1995 to 28 Mar 2023) in order to evaluate the false negative rate of thyroid nodules based on size and make recommendations for treatment of large thyroid nodules. False negative rates were highly variable (0–44% in small nodules; 0–77% in large nodules) and most studies (71%) did not recommend immediate surgical resection of large, cytologically benign nodules. We recommend that patients with cytologically benign but large thyroid nodules need not undergo immediate surgical resection because false negative rates are widely variable, are not significantly different based on nodule size, are highly institution- and pathologist-dependent, and have decreased in light of recent nomenclature recommendations. Close clinical follow-up can identify patients who ultimately require resection, and those with indolent disease may avoid surgery for cytologically benign but large thyroid nodules.