We describe our 5-year experience with percutaneous ethanol injection (PEI) for the treatment of cold benign thyroid nodules and report its efficacy and side effects. Fifty-four euthyroid outpatients (aged 44.8+/-12.7 years, mean+/-SD) were divided into two groups matched for sex, age, and nodule volume: 27 patients treated only by PEI and 27 patients treated additionally with levothyroxine-suppressive therapy (median follow-up: 24 months, range 6-48). Mean pretreatment nodule volume was 21.0 mL (range 5.4-54.6). Ethanol (1.3+/-0.6 mL/mL nodule volume) was injected under sonographic control in 4 to 13 weekly sessions (mean 7.4). PEI therapy was well tolerated by all patients. At the end of treatment, nodule volume was 7.7+/-5.7 mL (p = .0001). A further significant shrinkage was obtained at 1-year follow-up (4.4+/-3.8 mL; p < .05). No significant differences in nodule reduction were observed between the levothyroxine treated or untreated group and between patients with pretreatment nodule volume smaller or larger than 15 mL. Our study confirms the efficacy and safety of PEI in inducing volume shrinkage of cold benign thyroid nodules. Overall our data suggest that PEI may become an interesting alternative for patients with surgical indications, if they refuse surgery or are poor surgical risks, or eventually demand treatment for aesthetic purposes. It may also be considered when levothyroxine therapy is contraindicated or ineffective.