OBJECTIVE Fine-needle aspiration biopsy is regarded as the most important diagnostic tool for thyroid lesions because of its simplicity, safety, and cost-effectiveness. However, its pivotal role in the correct characterization of the majority of nodules is impaired by the difficulties in discriminating benign from malignant follicular-patterned lesions. METHODS Liquid-based cytology (LBC) is a semiautomated device that has recently become widely available and has gained popularity as a method of collecting and processing both gynecologic and nongynecologic cytologic specimens. It achieves a diagnostic sensitivity as accurate as conventional preparations, especially for its excellent cell preservation and lack of background which decrease the amount of inadequate diagnoses. RESULTS In many cases the cytologic features are similar in both methods, but the colloid film and the lymphocytic component are more easily evaluated on direct smears whereas nuclear details and colloid globules are better evaluated in LBC slides. The material stored in the preservative solution could be effectively used for the application of immunocytochemical and molecular techniques. CONCLUSIONS LBC-processed biopsies represent a valid alternative to conventional cytology. The possibility of applying additional techniques enhances the efficacy of the cytologic diagnosis of thyroid lesions.