The aim of the present study was to assess whether I-131 therapy for differentiated thyroid carcinoma (DTC) can affect endocrine testicular function. Methods: Serum follicle-stimulating hormone (FSH) and testosterone (T) concentrations were measured in 103 patients periodically submitted for radioiodine therapy for residual or metastatic disease. Mean follow-up was 93.7 +/- 54 mo (range 10-243 mo). Results: Mean FSH values in I-131-treated patients tested after their last treatment were 15.3 +/- 9.9 mU/ml, significantly higher than those of 19 untreated patients (6.5 +/- 3.1 mU/ml). Considering the mean +3 s.d. FSH of untreated subjects as the upper limit of normal range, 36.8% of the patients had an abnormal increase in serum FSH. Longitudinal analysis performed in 21 patients showed that the behavior of FSH in response to I-131 therapy was not universal. Six patients had no change or a slight increase in serum FSH after I-131 administion; eleven patients had a transient increase above normal values 6-12 mo after I-131 treatment, with return to normal levels in subsequent months. The administration of a second dose was followed by a similar increase in FSH levels. Finally, four patients, followed for a long period of time and treated with several I-131 doses, showed a progressive increase in serum FSH, which eventually became permanent. Semen analysis, performed in a small subgroup of patients, showed a consistent reduction in the number of normokinetic sperm. No change was found in serum T levels between treated and untreated patients. Conclusions: Our results indicate that I-131 therapy for thyroid carcinoma is associated with transient impairment of testicular germinal cell function. The damage may become permanent for high-radiation activities delivered year after year and might pose a significant risk of infertility.