To ascertain the clinical effect of discontinuation of thyroxine (T4) suppression therapy in patients with solitary thyroid nodules or multinodular goiters (MNGs).After long-term T4 suppression therapy was discontinued (desuppression) in 63 patients (45 with solitary or dominant nodules and 18 with MNGs), we conducted a prospective follow-up for a mean of 18 months in an effort to detect any thyroid-related changes.A dominant nodule developed in 4 of 18 patients with MNGs. Fine-needle aspirations showed benign lesions in these four patients, but two were referred for thyroidectomy because of substantial nodule growth (both lesions proved to be benign). Of the 45 patients with solitary or dominant thyroid nodules, 4 were lost to follow-up, and 9 had clinically significant nodule enlargement and underwent thyroidectomy. One patient had clinically significant papillary carcinoma, and one had microscopic papillary carcinoma.These data on effect of discontinuation of T4 suppression therapy suggest that (1) about 20% of patients with MNGs will ultimately have thyroid nodule enlargement and (2) about 20% of patients with a solitary or dominant nodule will have nodule enlargement, of which approximately 20% will have papillary carcinoma.