The aim of the present study was to evaluate the efficacy of percutaneous ethanol injection therapy (PEIT) with special reference to dose response and symptom score and to describe side effects in a parallel-group randomized clinical trial with 6 months of follow-up, comparing 2 different treatment strategies. Sixty euthyroid outpatients with a benign solid and scintigraphically solitary cold thyroid nodule causing local discomfort were assigned to 1 session with a single intranodular injection of sterile 98% ethanol (PEIT-1, n = 30) or 3 weekly sessions with 1 injection of sterile 98% ethanol (PEIT-3, n = 30). In the PEIT-1 group, the pretreatment nodule volume was 9.9+/-5.7 mL (mean +/- SD). It decreased to 7.0+/-4.7 mL after 1 month, and 5.6+/-5.9 mL after 6 months (p = 3.2x10(-6)), and the ethanol dose given was 24.7%+/-7.5% of the pretreatment nodule volume. The overall reduction in nodule volume was 46%. In the PEIT-3 group the pretreatment nodule volume was 9.4+/-4.2 mL. It decreased to 5.9+/-3.5 mL 1 month after the last session, and 4.6+/-2.6 mL after 6 months (p = 4.0x10(-10)), and the cumulative ethanol dose given was 47.9%+/-21.3% of the pretreatment nodule volume. The overall reduction in nodule volume was 51%, and the difference between the 2 treatment regimens was 5.3%+/-5.5% (mean +/- SE of difference, p = 0.3). A satisfactory treatment dose, defined as a total intranodular spread of ethanol visualized on the monitor screen, was achieved in only 50%-60% of the sessions. This was due to pain that necessitated premature discontinuation of the injection and was apparently severe enough in 3 patients in the PEIT-3 group that they refused additional treatment. Twenty-two of 30 (73%) patients in the PEIT-1 group and 19 of 30 (63%) in the PEIT-3 group had a marked effect on symptoms at 6-month follow-up (p = 0.6). Side effects comprised transient thyrotoxicosis in 2 patients, permanent ipsilateral facial dysesthesia and increased flow of tears in 1 patient, paranodular fibrosis impeding subsequent surgery in 1 case and various degrees of pain and tenderness related to PEIT in nearly all. Major side effects were dose dependent. We conclude that PEIT is effective in inducing necrosis and reducing the volume of benign solid cold thyroid nodules. The additive effect of 2 additional doses compared with 1 dose is insignificant. The optimum management strategy has yet to be clarified. Limitations relate to the procedure being quite painful despite local anesthesia and the fact that side effects are in no way negligible, and therefore, a word of caution in routine use is advisable.