Hypothesis: All thyroid nodules 4 cm or larger should be surgically removed regardless of fine-needle aspiration biopsy (FNAB) results because of an unacceptably high rate of false-negative preoperative biopsy results in these large nodules. Design: Retrospective cohort study. Setting: Single-institution, tertiary academic referral center. Patients: A retrospective analysis was performed on all patients who underwent surgery for a thyroid nodule 4 cm or larger from May 1, 1994, through January 31, 2007. Main Outcome Measures: Preoperative FNAB results were correlated with final surgical pathologic results. The FNAB results were reported as nondiagnostic, benign, inconclusive (follicular neoplasm), or malignant, whereas the final surgical pathologic data were reported as benign or malignant. Results: Of 155 patients who underwent a thyroidectomy for a nodule 4 cm or larger, 21 patients (13.5%) had a clinically significant thyroid carcinoma within the nodule on final pathologic analysis. Preoperative cytologic testing of the mass was performed on 97 patients, and the results read as benign for 52, inconclusive for 23, nondiagnostic for 11, and malignant for 11. In lesions 4 cm or larger, 26 of 52 FNAB results reported as benign (50.0%) turned out to be either neoplastic (22) or malignant (4) on final pathologic analysis. Among patients with nondiagnostic FNAB results, the risk of malignant neoplasms was 27.3%. Conclusions: In patients with thyroid nodules 4 cm or larger, the FNAB results are highly inaccurate, misclassifying half of all patients with reportedly benign lesions. Furthermore, those patients with a nondiagnostic FNAB result display a high risk of differentiated thyroid carcinoma. Therefore, we recommend that diagnostic lobectomy be strongly considered in patients with thyroid nodules 4 cm or larger regardless of FNAB cytologic test results. ©2009 American Medical Association. All rights reserved.