Alpha-1 antichymotrypsin (ACT), a serine protease inhibitor, has been detected in several epithelial tumor cell types, but its role in response to therapy is not clear. We report here that exposure of primary head and neck squamous cell carcinoma (HNSCC)-derived cells (PCI-04A) to ionizing radiation (IR) or tumor necrosis factor-alpha (TNF-alpha) resulted in an increased level of ACT mRNA, although the induction patterns were different. IR treatment caused a transient stimulation of ACT mRNA, peaking at 3 h post-irradiation, whereas TNF-alpha-inducible ACT gene expression lasted for up to 24 h. The ACT mRNA was expressed in several epithelial and non-epithelial tumor cell types, and in different normal human tissues. In addition, when the ACT gene expression in PCI-04A cells was compared with the matched (from the same patient) metastatic HNSCC-derived cells (PCI-04B), increased steady-state level of the ACT mRNA was observed in PCI-04B cells. Taken together, these findings suggest that ACT may serve as an important marker for prognosis and therapy selection in HNSCC.