Objective To investigate the risk of hypothyroidism after radioiodine (I-131) treatment for hyperfunctioning thyroid nodules. Design Retrospective analysis of patients treated with I-131 for hyperfunctioning thyroid nodules and followed up for a maximum of 20 years. Patients A total of 346 patients treated with I-131 in the years 1975-95, for a single hyperfunctioning nodule. Measurements Hypothyroidism was defined as TSH levels > 3.7 mU/l. Kaplan-Meier survival analysis was used to analyse permanence of euthyroidism after I-131. A stepwise Cox proportional hazard model was used to identify factors influencing the progression to hypothyroidism. Results The cumulative incidence of hypothyroidism was 7.6% at 1 year, 28% at 5 years, 46% at 10 years and 60% at 20 years. Age (P < 0.01), 24-th I-131 uptake (P < 0.05) and previous treatment with methimazole (MMI, P < 0.1) were associated with a faster progression towards hypothyroidism, while thyroid and nodule size, thyroid status at diagnosis and degree of extranodular thyroid parenchymal suppression had no influence. In hyperthyroid patients with partial parenchymal suppression, however, previous MMI treatment was the most important prognostic factor (P < 0.01). Conclusions After 20 years of follow-up, 60% of patients treated with I-131 for a single hyperfunctioning nodule are hypothyroid. Factors increasing the risk of hypothyroidism are age, I-131 uptake and MMI pretreatment. The prognostic value of this last factor, however, depends on the degree of suppression of the extranodular thyroid parenchyma at the scan.