Connective tissue growth factor (CTGF or CCN2), which belongs to the CCN family, is a secreted protein. It has been implicated in various biological processes, such as cell proliferation, migration, angiogenesis, and tumorigenesis. In this study, we found that CTGF expression level was elevated in primary papillary thyroid carcinoma (PTC) samples and correlated with clinical features, such as metastasis, tumor size, and clinical stage. Overexpression of CTGF in PTC cells accelerated their growth in liquid culture and soft agar as well as protecting PTC cells from apoptosis induced by IFN-gamma treatment. Downregulation of CTGF in PTC cells inhibits cell growth in liquid culture and soft agar and induces the activation of caspase pathway and sensitized PTC cells to apoptosis. Our data suggest that CTGF plays an important role in PTC progression by supporting tumor cell survival and drug resistance, and CTGF may be used as a potential tumor marker for PTC diagnosis.