Although the prognostic significance of occult lymph node metastases in thyroid cancer remains controversial, identifying these patients may help direct therapy. The purpose of this study was to determine the feasibility and safety of sentinel lymph node biopsy (SLNBx) in thyroid nodular disease. Patients undergoing thyroid resection, with no evidence of clinical lymphadenopathy, were enrolled. The nodule was injected with isosulfan blue vital dye. Blue-stained lymphatic channels were traced within the central compartment to the SLN, which was excised. A total of 40 patients underwent SLNBx; lymphatics were seen in 31 patients, and SLNs were found in 26. In 11 patients the lymphatic vessels were traced through the central compartment into the lateral or mediastinal compartments, although a central SLN was retrieved in only 6. Of the 18 patients with benign neoplasms, 14 had benign SLNs, and no SLN was found in 4. A thyroid lymphoma patient had a true positive SLN. In the 12 patients with papillary thyroid cancer (PTC), 6 had true positive SLNs, and 2 had a true negative SLN. In one patient with metastatic PTC, the parathyroid stained blue. Another patient with PTC had lateral lymphatic channels, but no SLN was found. There were two false negatives, proven by a node dissection in one and lateral uptake on (131)I scanning in the other. There were no postoperative complications. SLNBx for thyroid disease is feasible and safe. Potential staining of the parathyroids makes their identification before injection mandatory. The variable lymphatic drainage patterns and the two false-negative nodes indicate that further investigation is required before the procedure can be recommended for patients with thyroid disease.