Objective To observe and compare the different orthotopic models of papillary thyroid cancer ( PTC) cell lines of RET/PTC1 rearrangement and BRAFV600E mutation in nude mice. Methods Human PTC cell lines TPC-1, BHP5-16 and BHP2-7 were used. The genotypes of RET/PTC1 rearrangement and BRAFV600E mutation were determined by realtime-PCR and DNA sequencing analysis. The cells(2×105) were injected into the thyroid gland of nude mice. The nude mice were executed at 4th, 12th week, and then their thyroid tumors were removed and weighed. The levels of thyroid hormone were detected using chemiluminescent immunoassay. Results Both TPC-1 and BHP2-7 cells were identified as RET/PTC1 rearrangement by real time-PCR, and the expression of RET/PTC1 rearrangement in BHP2-7 cell was higher than that of TPC-1 cell. BRAFV600E mutation was found in BHP5-16 cell by DNA sequencing analysis, but was not found in TPC-1 and BHP2-7 cells. There were different characteristics in three orthotopic nude model groups. Tumorigenic rates of TPC-1 and BHP5-16 groups were 100%, but the growth of tumor was more rapid in BHP5-16 group than that in TPC-1 group, with more weight tumor. The changes of thyroid hormone levels in BHP5-16 group and TPC-1 group were the same, which were normal at 4th week and sharply decreased at 12 th week(P<0. 05). However, the tumorigenic rate of BHP2-7 group was only 6. 25%. Compared with normal control group, there was no statistical difference in the levels of thyroid hormone in BHP2-7group(P>0. 05). Conclusions It showed difference in the orthotopic models of PTC cell lines of RET/PTC1 rearrangement and BRAFV600E mutation in nude mice. BRAFV600E mutation has obvious impacts on increasing tumorigenic rate and promotion of tumor growth in the orthotopic model. It should not be ignored that advanced thyroid tumor will lead to the destruction of thyroid function.