Thyroid nodules are prevalent; when evaluated by ultrasonography (US), 15-25% of solitary thyroid nodules are cystic or predominantly cystic, and most are benign. Simple aspiration is the treatment of choice, but the recurrence rate is 10-80% depending on the number of aspirations and the cyst volume. The aim of this study was to evaluate the effect on recurrence rate of benign recurrent thyroid cysts in a double-blind randomized study comparing ethanol instillation with instillation of isotonic saline and subsequent complete emptying. Sixty-six consecutive patients with recurrent and benign (based on US-guided biopsy) thyroid cysts (>or=2 ml) were randomly assigned to either subtotal cyst aspiration, flushing with 99% ethanol, and subsequent complete fluid aspiration (n = 33), or to subtotal cyst aspiration, flushing with isotonic saline, and subsequent complete fluid aspiration (n = 33). In case of recurrence (defined as cyst volume >1 ml) at the monthly evaluations, the treatment was repeated but limited to a maximum of three treatments. Procedures were US-guided, and patients were followed for 6 months. Age, sex, number of previous aspirations, pretreatment cyst volume, and serum TSH did not differ in the two groups. Cure (defined as a cyst volume <or=1 ml at the end of follow-up) was obtained in 27 of 33 [82%; confidence interval (CI), 65-93] patients treated with ethanol and in 16 of 33 (48%; CI, 31-66) patients treated with saline (P = 0.006). In the ethanol group, 21 of 33 (64%) patients were cured after one session only, compared with six of 33 (18%) in the saline group (P = 0.002). The number of previous aspirations (P = 0.005) and baseline cyst volume (P = 0.005) had influence on outcome, i.e. the chance of success decreased with the number of previous aspirations and with increasing cyst volume. Seven patients (21%) treated with ethanol had moderate to severe pain (median duration, 5 min; CI, 2-10), and one had transient dysphonia. Indirect laryngoscopy was performed before and after the last session and was normal in all patients. We concluded that treatment of recurrent thyroid cysts with ethanol is superior to simple aspiration and flushing with saline and devoid of serious side effects. Our study demonstrates that flushing with ethanol is a clinically significant nonsurgical alternative for thyroid cysts that recur despite repeat aspirations.