In spite of much effort, no good markers have yet been found for predicting prognosis or response to therapy in advanced head and neck squamous cell carcinoma (HNSCCs) patients. β-catenin, a protein involved in the cytoskeleton, cell–cell adhesion and gene transcription, is a factor associated with tumour progression. Recently, an interaction has been reported between β-catenin, and NF-κB coupled with an inverse association of β-catenin, and FAS (CD95/APO-1) protein expression in breast and colorectal tumours. To confirm these observations and to test their clinical impact in HNSCCs we have evaluated the expression of β-catenin, NF-κB and FAS proteins. We used tissue microarrays to simultaneously analyse the levels of these proteins immunohistochemically in 118 HNSCCs. Among the 113 tumours evaluable for β-catenin, increased and decreased levels were detected in 41 (36%) and 62 (55%) of the tumours, respectively. β-catenin, protein staining was mainly membranous but 10 tumours (9%) showed the clear presence of protein in the cytoplasm, and none in the nucleus. Moreover, 81% of the tumours had decreased FAS protein expression, indicating that loss of FAS protein is a common feature of HNSCCs. Abnormal or nuclear NF-κB staining was observed in 24% of the tumours. No association was detected between the expression levels of the proteins evaluated. Regarding clinical associations, tumours from the hypopharynx had significantly lower levels of β-catenin expression than those from other locations (P<0.05). Moreover, our data revealed that patients whose tumours had low levels of β-catenin protein expression had decreased survival probability (24.8 months vs. NR, P=0.03) and reduced response to therapy (15.4 vs. 43 months; P=0.01) compared with patients whose tumours had high levels of β-catenin. Taken together, our observations indicate that β-catenin, NF-κB and FAS expression are independent events during HNSCC development and that levels of β-catenin protein may identify subsets of advanced HNSCCs patients with different prognosis and response to therapy capabilities.