We have shown that both tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta1 (TGF-beta1) inhibit the growth of the human papillary thyroid carcinoma (PTC) cell line, NPA. In previous work, we developed NPA cells that were resistant to the growth suppressive effect of TNF-alpha, called R30, R45, and R60. In this model there were alterations in the p55 and p75 TNF-alpha receptor signaling in the resistant cell lines. In the present work, we studied the action of TGF-beta1 in this PTC cell model. TGF-beta1 (111 pg/mL) inhibited the proliferation of NPA, R30, R45, and the R60 cell lines by 82.8%, 72.1%, 64.2%, and 24.2%, respectively. On Western analysis, TGF-beta1 reduced c-fos content with similar potency in the NPA and R60 cells. In contrast, TNF-alpha reduced c-fos content in the sensitive NPA cells, but failed to do so in the resistant R60 cells. TGF-beta1 reduced p53 content in the NPA but not in the R60 cells, while TNF-alpha did not affect the p53 content in these cells. Furthermore, the resistant cells had a lower baseline p53 content than the NPA cells. The resistant cells had a significantly increased growth rate. Enzyme-linked immunosorbent assay (ELISA) assays with specific antibody against human p53 showed no apparent increase in the mutant form of p53 in the resistant cells. There were also no mutant forms of Ha-Ras, Arg12p21, Val12p21, Asp12p21, and Asp13p21 detected in the resistant cells. The results showed that R30, R45, and R60 cells are partially resistant to TGFbeta1. The mechanisms of action of TNF-alpha and TGF-beta1 differ in their regulation of c-fos and p53 content. The increase in cell proliferation rate is apparently associated with a decrease of p53 content, but not with mutations of p53 or Ha-Ras.