Percutaneous ethanol injection (PEI) was first proposed about 30 years ago for sclerotherapy of different kind of lesions, such as hepatocellular carcinoma, hepatic and renal cysts, adrenal adenoma, and parathyroid hyperplasia. Ethanol exerts its sclerosing properties through cellular dehydration and protein denaturation, which lead to coagulative necrosis and small vessel thrombosis. As a consequence, hemorrhagic infarcts and reactive fibrosis are the prevailing histological changes described in tissues exposed to ethanol. In the thyroid gland, the first documented use of PEI for treating thyroid cysts dates to 1989 (Period Biol 91:1116–1118, 1989); shortly after, this technique was also suggested as an alternative therapeutic option to surgery and radioiodine for the treatment of autonomous functioning nodules. Since then, PEI sclerotherapy of thyroid cysts has gained a world-wide diffusion, whereas the fortunes of PEI as a candidate first-line therapy for toxic and pre-toxic solid nodules have gradually faded. PEI treatment of thyroid cysts will therefore constitute the heart of the present chapter. PEI has also proved to be quite effective in treating other neck lesions, like thyroglossal duct cysts, enlarged parathyroid glands, and metastatic lymph nodes. These applications of PEI will also be briefly discussed.