Radioiodine (131I) represents an interesting alternative to surgery in the treatment of autonomously functioning thyroid nodules (AFTN), but leads to a significant incidence of hypothyroidism when high doses are used. Over 4 years, we have treated 40 patients (hyperthyroid [Plummer's disease]: 6, single hot nodules with undetectable thyrotropin [TSH] and normal serum free thyroxine [FT4]: 34), 34 single hot nodules with undetectable thyrotropin TSH and normal serum free thyroxine [FT4] with 131I. The dose level was neither related to the concentration of FT4 nor to the iodine uptake on thyroid scintigram. Retrospectively we measured the nodule's area on the scan and calculated the dose/area ratio (DAR). Three months after treatment, 30 patients were euthyroid, 9 were still hyperthyroid, and 1 was hypothyroid. The mean DAR of the euthyroid patients was twofold higher than for the hyperthyroid subjects (1.4 +/- 0.8 vs. 0.7 +/- 0.3 mCi/cm2; p = .003) and one-half the DAR for the hypothyroid patient (2.82 mCi/cm2). Twenty of the 30 euthyroid patients had received a dose higher than 1 mCi/cm2 and 7 of 9 hyperthyroid patients had received a dose lower than 1 mCi/cm2. (chi2 = 12.9; p = .02). The initial values of T4, TSH, and dose level of patients who were euthyroid or hyperthyroid at 3 months were not different. These data suggest that the efficacy of 131I for treating AFTN depends on the DAR, rather than the initial T4 value or the 131I uptake. A DAR between 1 and 1.5 mCi/cm2 seems to be optimal and avoids hypothyroidism.