Percutaneous injection of alcohol was recently proposed as an alternative to surgical and radioiodine treatments of autonomous thyroid nodules. The purpose of this study was to determine the value of this procedure and to define its limitations and indications when used for this purpose. Thirty-one patients with autonomous thyroid nodules underwent a cycle of treatment with percutaneous injection of ethanol in multiple sessions (three to seven) on alternate days depending on the diffusion of the ethanol in the nodule. Fifteen patients were hyperthyroid, and 16 were euthyroid but had inhibited secretion of thyrotropin. The treatment results were evaluated by thyroid scintigraphy and sonography, by triiodothyronine, thyroxine, and thyrotropin assays, and by a thyrotropin-releasing hormone stimulation test 6 months after the end of treatment. Baseline scintigraphy demonstrated exclusive radionuclide uptake in the nodule in 29 patients and partial uptake in the extranodular tissue in two. The volume of the nodules ranged from 0.8 to 34.0 ml (mean +/- SD, 11.8 +/- 8.8 ml). Patients were monitored clinically for 24 hr after each session of ethanol injection to evaluate complications. Fifteen patients underwent a second cycle of ethanol injection when the results 6 months after the first cycle were unsatisfactory. The mean +/- SD follow-up was done at 26.9 +/- 12.3 months. Scintigraphy showed recovery of extranodular uptake of radionuclide in 72% of patients with nodules less than 13 ml in volume (maximum diameter [mean +/- SD], 2.7 +/- 0.7 cm; range, 1.4-4.0 cm) after one cycle of treatment and in 83% after two cycles. Among subjects with larger nodules, radionuclide uptake returned to normal in 9% after one cycle of treatment and in 9% after two cycles. For hyperthyroid patients, levels of thyroid hormones returned to normal in 69% after one cycle and in 77% after two cycles, and levels of thyrotropin returned to normal in 38% after one cycle and in 69% after two cycles; normal levels of thyrotropin were achieved in 93% of the euthyroid patients after one cycle of treatment and in 100% of these patients after two cycles. Symptoms resolved in 73% of the hyperthyroid subjects after the first cycle of treatment and in 93% of these subjects after the second. No important complications were observed; the most common side effects were acute pain at the injection site, referred pain, fever, transient dysphonia (< 12 hr), local hematoma, palpitations, and sinus tachycardia. Our results show that percutaneous injection of ethanol is appropriate therapy for autonomous thyroid nodules less than 13 ml in volume. The treatment should be considered successful when levels of thyroid hormones and thyrotropin return to normal. Nodule size appears to be the most important determinant of the success of the treatment. No complications that required termination of the treatment occurred.