We evaluated the role of first (131)I-whole-body scan and of first serum thyroglobulin (Tg) measurement after surgery in the early diagnosis of metastases from differentiated thyroid carcinoma (DTC). METHODS In 269 patients with metastases from DTC, we retrospectively evaluated the results of first whole-body scan (performed 40 days after surgery with diagnostic or therapeutic (131)I dose) and in 69 of them we also evaluated the result of first Tg measurement (performed the day before the first whole-body scan) in relation to the presence, localization and type of metastases. RESULTS In all patients, the first whole-body scan was positive for the thyroid remnant, and in 54.3% of patients it was also positive for metastases. In the remaining 45.7% of patients, metastases were detected during the follow-up. First Tg levels were >60 ng/ml in 66.7% of patients with metastases. First whole-body scan detected metastases in 47.8% of patients with Tg values <60 ng/ml, while Tg values were >60 ng/ml in 61.3% of patients with first whole-body scan negative for metastases. The combined results of both first whole-body scan and first Tg measurement allowed the early detection of metastases in 82.6% of patients. Whole-body scan detected distant metastases more frequently than local lymph node metastases (p < 0.01). CONCLUSIONS In more than 80% of patients, metastases were suspected or diagnosed as early as 40 days after surgery in the presence of residual thyroid tissue by combined evaluation of results of first whole-body scan and Tg measurement.