We present a prospective study on the long-term efficacy of percutaneous ethanol injection (PEI) treatment for thyroid cystic nodules. Among patients referred for symptomatic thyroid cystic nodules who had relapsed after two aspirations or whose nodules could not be aspirated due to the thickness of the cystic fluid, PEI was given when surgery was either refused or contraindicated. Forty-three patients were treated; the mean basal volume of the cysts was 38.4 mL. The purpose of the study was to evaluate long-term efficacy of PEI treatment on: (1) amelioration of symptoms and signs of local compression and (2) nodule volume reduction. In three subjects (7%), PEI failed to induce a significant (>50%) nodule reduction, so that surgical treatment was performed. In 40 patients (93%), an impressive nodule shrinkage was observed, reaching a plateau after 24 months (volume reduction = 91.9%+/-11.4%). A new PEI session was needed in two patients in whom a recurrence was noted within the first 6 months. After 6 months, no significant (> or =1 mL volume) nodule regrowth was observed up to 60 months. Both symptoms and tracheal displacement rapidly (within 1 month) and significantly (p<0.01) improved. After PEI, mild pain was the only side effect observed. No suspicious cytology was observed in any residual nodule greater than 1 mL 6 and 24 months after the last PEI session. Our data suggest that PEI is a first-line safe, effective, probably definitive, treatment for cystic thyroid nodules for which surgery is either refused or contraindicated.