Thyroid cancer (TC) is a common malignancy of the endocrine system. Abnormal expression of tripartite motif-containing 29 (TRIM29) has been reported to promote tumorigenesis and predict poor prognosis in several human malignancies. The aim of this study was to assess the involvement of TRIM29 in the significance and prognosis of TC. Fifty-six tumor samples and their clinicopathological para-meters were obtained from TC patients; the expression level of TRIM29 was detected by RT-qPCR and western blotting. TRIM29 expression was knocked down by small interfering RNA (siRNA) among TT, TPC-1, and K1 cells to investigate the biological role of TRIM29 in TC cells. The results showed that TRIM29 expression was significantly increased in TC tissue samples and cells compared to normal tissues and cells (P<0.01, respectively). Overexpression of TRIM29 was associated with TNM stage (P<0.01), extrathyroidal extension (P<0.01), lymph node metastasis (P<0.05), and distant metastasis (P<0.05). Furthermore, the overall survival and disease-free rates of patients with high TRIM29 expression were decreased significantly compared with those with low TRIM29 expression (P<0.01, respectively). Knockdown of TRIM29 obviously suppressed cell proliferation; enhanced chemosensitivity to cisplatin; inhibited cell invasion and migration; caused cell cycle arrest at G0/G1 phase by decreasing cyclin B1, cyclin D1 and CDK2, while increasing p21 and p27; and induced cell apoptosis by enhancing the activities of caspase-3, caspase-9, and Bax, while decreased Bcl-2. Notably, decreased TRIM29 expression significantly inhibited the activation of P13K/AKT signaling pathway as well. Taken together, our findings suggested that TRIM29 played a crucial role in the progression and malignancy of TC, and silencing of TRIM29 exerted its antitumor effect by blocking P13K/AKT signaling pathway. Thus, TRIM29 might be a potential therapeutic target for the treatment of TC.