In a prospective study, 53 consecutive patients with solitary thyroid cysts were randomized to ultrasonically guided cyst aspiration and subsequent flushing with isotonic saline (n = 30) or tetracycline hydrochloride (n = 23). The patients were followed up clinically and ultrasonically 1, 3, 6, and 12 months after treatment. If the cyst recurred, a repeated treatment was offered. Cure was defined as the absence of any residual nodule and an ultrasonic cyst volume of less than 1 mL 12 months after the last treatment. During follow-up, two patients without recurrence after saline treatment and six patients without recurrence after tetracycline treatment developed solid cold nodules. Fourteen (47%) of 30 patients in the saline group and ten (43%) of 23 patients in the tetracycline group were cured (not statistically significant). Tetracycline does not seem to offer any advantage over isotonic saline in the treatment of thyroid cysts, and some of these patients still need thyroid surgery.