Abstract: Objective In recent years, the incidence of papillary thyroid carcinoma (PTC) increased gradually and the recurrence and metastasis of PTC patients are also increasing. The aim of this study was to investigate the effect of BRAF^V600E mutation on the expression of HMGB1 in PTC, to explore the mechanism of BRAF gene affecting the development and prognosis of PTC, and then guiding clinical practice of precise therapy. Methods The preoperative serum and postoperative fresh tissue were collected from 44 cases of PTC patients in our hospital from September, 2015 to December, 2015. According to BRAF^V600E mutations divided into positive group and negative group. Western blot, immunohistochemistry and fluorescence quantitative PCR were used to detect the level of HMGB1 in cancer tissues. The level of HMGB1 in serum was tested by ELISA method. Western blot was performed using Image J software. The relative quantitative method was used to calculate the fluorescence quantitative PCR data. The concentration of HMGB1 protein in serum was calculated by ELISA Calc regression/fit calculation program. All the data were analyzed by SPSS 20. 0. Western blot, fluorescence quantitative PCR and ELISA data were analyzed by Chi-square test, Mann-Whitney-Wilcoxon test and independent sample t test. The relationship between lymph node metastasis and extrathyroid infiltration and the occurrence of BRAF^V600E mutation was analyzed by chi-square test. Results In PTC cancer tissues, HMGB1 was mainly located in the cytoplasm, the levels of HMGB1 mRNA and protein in positive group were lower than that of the negative group (Z=2. 117, P < 0. 01, χ²=19. 989, P < 0. 05), and the change did not show in peripheral blood (t=1. 135, P > 0. 05). The expression of HMGB1 mRNA and protein in PTC with lymph node metastasis was lower than those without lymph node metastasis (Z=-2. 216, P < 0. 05; t=-2. 217, P < 0. 05), and so as in the extrathyroid infiltration (Z=-2. 267, P < 0. 05; t=-3. 885, P < 0. 01). Conclusion BRAF^V600E mutations may accelerate the malignant development of PTC by down regulating the expression of HMGB1.