Purpose This study was conducted to assess the value of sonographically guided core biopsy in the evaluation of thyroid nodules by comparison with fine‐needle aspiration cytology (FNAC) performed with and without sonographic guidance. Methods We performed a retrospective analysis of a consecutive series of 645 thyroid samples obtained at a single center. Samples came from 422 patients who underwent FNAC (with or without sonographic guidance), sonographically guided core biopsy, or excision of thyroid tissue with or without prior frozen sectioning. Final diagnoses were obtained from surgery or clinical follow‐up. Initial and final diagnoses were compared. Results Adequate samples for assessment were obtained in 87% of core biopsies, compared with 60% of cytology aspirates (p < 0.001). Sonographically guided core biopsy and sonographically guided FNAC both had zero false‐negative rates for the diagnosis of malignancy, compared with a 7.0% false‐negative rate (95% confidence interval, 2.0–12.0%) for aspiration cytology when sonography was not used. With core biopsy, 11% of patients required surgical confirmation of the diagnosis, compared with 43% of patients following FNAC (p < 0.001). There were no major complications following core biopsy. Conclusions Sonographically guided core biopsy provides an accurate and safe alternative to FNAC in the assessment of thyroid nodules. © 2005 Wiley Periodicals, Inc. J Clin Ultrasound 33:57–62, 2005