We report a case in which the appearance of a progressively rising titer of thyroglobulin (Tg) antibodies was the most sensitive marker of papillary thyroid cancer relapse at loco-regional lymph nodes. The patient, a 60-year-old man, had been treated with total thyroidectomy plus lymphadenectomy and radioiodine ablation for a 1-cm papillary thyroid cancer. Twelve years after surgery, while undergoing levothyroxine (LT4) therapy, Tg antibodies were first detected and progressively rose from 99 to 1,697 U/mL in 18 months, while serum Tg remained undetectable. Both neck ultrasonography and 131I whole-body scan (WBS) were unremarkable. Enlarged lymph nodes became palpable at the left laterocervical region only 2 years after the first appearance of Tg antibodies and were surgically removed after cancer relapse was confirmed by fine-needle aspiration cytology. This case emphasizes the possibility that in thyroid cancer patients who have undergone total thyroidectomy, the appearance of Tg antibodies may indicate metastatic lymph nodes even when serum Tg is undetectable and WBS negative.