We studied the effect of percutaneous ethanol injection (PEI) in the treatment of cold, cytologically benign, large (>10 mL) thyroid nodules (CBNs) in 41 patients. The end-point of our study was to evaluate the efficacy of PEI on: 1) local symptomatology, assessed by an arbitrary symptom score; and 2) nodule volume and tracheal displacement (at ultrasonography). Follow-up ranged from 12-36 (21 +/- 9) months. Symptom score was significantly reduced (P < 0.01) after 6 months and at the end of the follow-up (2.1 +/- 0.3 vs. 0.2 +/- 0.5 and vs. 0.2 +/- 0.4). A significant (P < 0.01) nodule volume reduction was observed, without differences between solid or mixed CBNs; the reduction was 50% or more in 92.7% of patients. Neither clinical parameters nor pretreatment nodule ultrasonographic features were related to nodule reduction. Disappearance or significant reduction (>0.5 cm) of tracheal displacement was obtained in 61% and in 39% of patients, respectively. One patient experienced prethyroid region edema, pain, and mild fewer, which reversed within 1 week; and one patient had dysphonia, caused by vocal cord palsy, which reversed spontaneously within 1 month. At the end of the follow-up, nodules with just necrotic material at cytology showed a greater (P < 0.05) volume reduction than nodules with residual benign thyroid cells. Our data suggest that PEI is a safe and effective treatment of large CBNs, although sometimes serious side effects do occur.