The TGF-beta and the p53 pathways are crucial pathways in controlling cell growth and differentiation. Defects in TGF-beta signaling including mutations in the Smad4 gene have been associated with cancer in humans and aberration of the p53 pathway is often found in oral cancer. Objectives: we investigated the integrity of the TGF-beta and the p53 pathways using a series of cell lines derived from oral squamous cell carcinoma (OSCC) that were not subjected to radiation or chemotherapy. Methods: Immunoblot analysis was performed for the determination of Smad4 and p53 protein levels. DNA damage was also induced in these cell lines using actinomycin D. Results: We found that the steady state levels of Smad4 protein in all SCC cell lines were lower than that of normal oral keratinocyte control. Accumulation of p53 protein was observed in SCC4, SCC66 and SCC68 indicating that p53 may be mutated in these lines. On the contrary, p53 steady state protein levels were undetectable in SCC25, SCC71 and SCC111. To rule out p53 deletion in SCC25, SCC71 and SCC111, these cells were treated with actinomycin D, a DNA damaging agent that usually induces p53 expression. At 48 hours after treatment with a sublethal dose of actinomycin D, p53 could be detected in SCC71 and SCC111. In SCC25, p53 protein levels remained undetectable indicating that p53 gene may be non-functional or deleted. Conclusion: These results suggest that the TGF-beta and the p53 pathways may be deregulated in OSCC cell lines.