© 2022Objective: There is controversy about whether the rates of malignancy and of false-negative malignancy are greater in large nodules. The aim of this study was to determine the reliability of cytology in ≥ 4 cm nodules and to compare malignancy rates between ≥ 4 cm and < 4 cm nodules. Methods: The study included 1205 patients who underwent biopsy and subsequent thyroidectomy with the diagnosis of nodular thyroid disease between 2014 and 2019. The patients were separated into two groups, ≥ 4 cm and < 4 cm, according to the size of the index nodule on ultrasonography. Results: Two hundred and eleven index nodules (17.5%) were ≥ 4 cm. Malignancy rate on definitive pathology was 51% in < 4 cm nodules and 30% in ≥ 4 cm nodules. Malignancy risk was significantly lower in ≥ 4 cm nodules than < 4 cm nodules (P < 0.001). When <1 cm nodules were excluded and 1–4 cm and ≥ 4 cm nodules were compared, malignancy risk was also significantly lower in ≥ 4 cm nodules (P = 0.001). On definitive pathology, there were 45 false-negative results among cytologically benign nodules. There was no difference in false-negative cytology rate between < 4 cm and ≥ 4 cm nodules (P = 0.209). Conclusion: The present study found no decrease in the reliability of cytology in ≥ 4 cm nodules, and there may not be a linear relationship between nodule size and malignancy risk. Therefore, in asymptomatic cytologically benign ≥ 4 cm nodules, surgery may not be recommended based on nodule size alone.