Relapses of hyperthyroidism after treatment with radioiodine for uni- or multi-nodular goiter may be accompanied by the appearance of TSAb. However, this phenomenon has only emerged from one retrospective study on Northern European patients, in which it was not possible to determine whether TSAb also appeared in treated patients who did not relapse. The present study aimed to assess the appearance, immunogenic nature and clinical characteristics of hyperthyroidism relapse after treatment with 131I for nodular toxic goiter in patients from the Mediterranean area. A retrospective study was performed on 76 consecutive patients, born and resident in Sicily and aged 56-80 yr at diagnosis, who were treated with radioiodine. Serum aliquots obtained from the patients before 131I treatment and during a follow-up of 36-144 months were assayed for TSAb and TPOAb. The clinical charts of the patients were also re-examined. Twenty-six out of 76 patients (36.8%) had a hyperthyroidism relapse after a first treatment with 131I. Eight of the 26 (30.7%) also relapsed after the second treatment. Three out of 26 (11.5%) relapsed after a third treatment. The 50 patients who required only one treatment and the 18 who relapsed only once were all TSAb-negative at baseline, while 3/8 (37.5%) who relapsed also after the second treatment were already TSAb-positive at baseline. TSAb became positive in 3/18 patients (16.7%) who relapsed once, and in 4/8 (50.0%) of those who relapsed after a second treatment. One of these 7 TSAb-positive relapsers was also already TPOAb-positive at baseline and another became TPOAb-positive after treatment. The presence of circulating TSAb in 3/76 (3.9%) patients before treatment for toxic goiter more probably points to a diagnosis of Marine-Lenhart's syndrome. In contrast, the de novo appearance of TSAb in the presence of hyperthyroidism relapse in 4/76 (5.3%) patients suggests the development of a Graves'-like disease after radioiodine treatment. This occurrence does not seem to have precise ethnic grounds, since the incidence we observed in Mediterranean patients was similar to that previously reported in Northern European patients.