The amplification of thyroglobulin (TG) mRNA in peripheral blood of patients with thyroid cancer has been studied for almost one decade, but its real contribution for diagnosis of cancer relapse has not yet been established. In the present paper we report the case of a patient with papillary thyroid cancer with undetectable stimulated serum thyrogobulin levels after thyroid ablation. Follow-up showed the presence of high titers of anti-thyroglobulin antibodies and the presence of TG mRNA in a peripheral blood sample, while cervical ultrasound and thorax and cervical computerized tomography were negative. Reinvestigation confirmed lymph node metastases. Anti-TG antibodies progressively decreased after surgery for metastatic lymph nodes resection followed by radioiodine therapy. Although our recent findings show that patients with positive TG mRNA do not have increased risk of cancer recurrence after 24 months of follow-up, the presence of TG mRNA along with high anti-TG antibodies were important indicators that determined further extensive investigation of tumour relapse in this patient, since positron emission tomography scan was not available at our Institution. A methodological standardization that can distinguish specific from non-specific TG mRNA amplification might be of great interest for the follow-up of differentiated thyroid cancer, especially in patients with high levels of anti-TG antibodies.