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Prophylactic central neck dissection (pCND) is controversial in papillary thyroid carcinoma (PTC) without clinical positive lymph nodes. The aim of this study was to investigate the effect of radioactive iodine (RAI) therapy on the clinical outcome in clinically node-negative (cN0) PTC patients treated with total thyroidectomy (TT) alone or in combination with pCND.One-hundred and sixty-seven cN0 PTC patients who underwent TT alone (TT) or in combination with pCND (TT+pCND) in our hospital from January 2014 to August 2015 were evaluated retrospectively. Adjuvant RAI therapy was recommended depending on tumor diameter, multifocality, extrathyroidal extension, the presence of positive lymph nodes, and adverse histopathologic features. Serological and imaging data were collected with a mean follow-up of 29.9±5.2 months after RAI administration. Suppressed and stimulated thyroglobulin, thyroglobulin antibody, diagnostic whole-body scintigraphy, and other imaging examinations were used to assess clinical outcome, which was defined as excellent response, indeterminate response, biochemical incomplete response, and structural incomplete response.TT was performed in 62 (37.1%) and TT+pCND in 105 (62.9%). The rate of permanent hypoparathyroidism was significantly higher in TT+pCND than that of TT alone (14.2 vs. 3.2%, P=0.0316). Because of the detection of central neck lymph node metastases by pCND, 42 (40%) patients developed higher recurrence risk stratification (from low to intermediate) and 12 (11.4%) patients were upstaged in TNM staging. RAI therapy was performed for 46 (74.2%) patients in the TT group and 87 (82.9%) in the TT+pCND group. The mean dose for patients receiving RAI in the TT+pCND group was significantly higher than that in the TT group (113.9±23.1 vs. 93.9±18.1, P<0.0001). No significant difference in response to RAI therapy was found between the TT group and the TT+pCND group (P=0.9474).Although the addition of pCND to TT, with a concomitant higher frequency of permanent hypoparathyroidism, upstages 40% of patients, thereby changing the dose of RAI therapy, the clinical response to RAI therapy for TT+pCND is not superior to TT alone in cN0 PTC patients.