BACKGROUND: Thyroid nodules are common and most often benign. The natural history of benign thyroid nodules, however, is unclear. OBJECTIVE: To determine the natural history of cytologically benign thyroid nodules using ultrasonography. DESIGN: Retrospective case series. SETTING: Single tertiary care clinic. PARTICIPANTS: All patients referred to the Brigham and Women's Hospital Thyroid Nodule Clinic, Boston, Massachusetts, who had benign cytologic results on ultrasonography-guided fine-needle aspiration of a thyroid nodule between 1995 and 2000 and returned for a requested follow-up examination 1 month to 5 years later. MEASUREMENTS: Nodule dimensions were measured at both visits, and growth was defined as an increase in calculated volume of 15% or greater. These results were correlated with the time between examinations, age, sex, baseline serum thyroid-stimulating hormone concentration, and cystic content of each nodule. RESULTS: Nodule volume increased over time (P < 0.001). The estimated proportion of nodules with an increase in volume of 15% or greater after 5 years was 89%. Nodules with greater cystic content were less likely to grow than solid nodules (P = 0.01). Seventy-four of the 330 nodules were reaspirated on the second visit. Despite an average increase in volume of 69%, only 1 of 74 reaspirated nodules was malignant. CONCLUSION: Most solid, benign thyroid nodules grow. Therefore, an increase in nodule volume alone is not a reliable predictor of malignancy.