The p53 homologue p63 produces six different isoforms that are important in development of epithelial tissues and squamous cell carcinoma of the head and neck (SCCHN). In SCCHN, the expression of p63 isoforms is highly complex, with over-expression of DeltaNp63 and p63beta isoforms in many tumours. To date, little is known about the functions of different DeltaNp63 isoforms and elucidating the distinctive properties of DeltaNp63 isoforms will help to clarify how they influence tumour biology. By gene expression profiling of SCCHN cells over-expressing the DeltaNp63 isoforms we identified different effects of the three isoforms, with DeltaNp63beta being more effective at gene induction than DeltaNp63alpha and DeltaNp63gamma, whereas DeltaNp63gamma was most effective at repressing gene expression. Thus, tumours expressing even low levels of DeltaNp63beta or DeltaNp63gamma may have distinct clinicopathological characteristics important for metastasis and therapeutic response. Induction of cyclooxygenase-2 (Cox-2) was shown by each isoform and data were confirmed by independent quantitative RT-PCR and western blotting. No direct binding of DeltaNp63 to the Cox-2 promoter could be seen, neither could any evidence for Cox-2 induction as a consequence of activated NF-kappaB pathway responses be found. As Cox-2 is known to inhibit radiotherapy responses in SCCHN patients, data indicate an additional mechanism through which DeltaNp63 acts to promote cell survival and influence therapeutic response of SCCHN. MIAME-compliant data have been deposited in the MIAME Express database (Accession No. E-MEXP-1842).