In patients with solitary thyroid nodules (TN) undergoing surgery both fine-needle aspiration (FNA) and frozen-section examination (FSE) are currently performed, but their role is still controversial. We retrospectively analyzed a series of 606 patients with a nontoxic solitary thyroid nodule who underwent both FNAB and FSE prior to thyroidectomy. There were 118 (19.5%) men and 488 (80.5%) women, with a median age of 44 years (range 16-81 years). The results of both FNAB and FSE were compared against the final pathological examination. Definitive histology showed 500 (82.5%) benign nodules, including 239 (39.4%) follicular adenomas, and 106 (17.5%) carcinomas, of which 18 (17.0%) were follicular cancer. In differentiating between benign TN and thyroid tumors the sensitivity, specificity, and accuracy of FNAB were 93.6%, 98.9% and 95.9%, while in the detection of malignancy were 81.1%, 99.4% and 96.2% for FNAB, and 83.0%, 100% and 97.0% for FSE (P = NS), respectively. The combination of both techniques did not improve significantly (P = NS) the results. Both medullary and undifferentiated cancer, and 76 of 80 (95.0%) papillary carcinomas were correctly detected by FNAB. Three (0.5%) false-positive smears suggesting cancer were found. In conclusion, in patients with FNAB revealing thyroid cancer or a benign TN, the extent of thyroidectomy should be established by performing FSE. When FNAB suggests the presence of a follicular tumor, FSE may affect rarely the final intraoperative decision-making, and should be considered unnecessary. However, in patients with FNA revealing thyroid cancer, FSE is useful in confirming malignancy, and may avoid surgical overtreatments.