The aim of this study is to define the diagnostic role of Liqui-Prep (LP) technique for the diagnosis of thyroid lesions and to assess interobserver variabilities. In all, 98 thyroid FNA (fine needle aspiration) cytology samples from 83 patients for preoperative evaluation of thyroid nodules, prepared by the LP, were examined. The LP slides were independently evaluated by three pathologists and they were classified into the five categories according to the Bethesda system. The histopathologic diagnoses were grouped as follows: benign, follicular neoplasm, and malignant. Agreements between LP and histopathologic diagnoses were investigated using kappa values. Marginal homogenity and kappa tests were used for statistical analysis for the evaluation of the agreement between the pathologists and the interobserver variability of the thyroid aspiration cytology results. The presence of nucleoli, nuclear grooving, overlapping, intranuclear inclusion, and nuclear irregularity were recorded and scored on each case based on LP slide review. Concurrences between LP and the histologic diagnoses for the three pathologists were almost perfect (k = 0.798; k = 0.826; k = 0.880). When the observers were paired there was no significant difference from the diagnostic point of view. Interobserver agreement among the three pathologists was moderate. Initially diagnostic difficulties may occur because of the inadequate experience of the pathologists concerning the evaluation of the cytologic changes associated with this new technique. Liqui-Prep technique is useful for the cytologic diagnosis of the thyroid nodules. The nuclear irregularity was the most essential feature for the differentiation of malignant lesions from follicular neoplasm by the LP method. Diagn. Cytopathol. 2011; © 2011 Wiley-Liss, Inc.