The TP63 gene, a TP53 homologue, encodes for two main isoforms by different promoters: one retains (TA) and the other lacks (DeltaN) the transactivation domain. p63 plays a critical role in the maintenance of basal and myoepithelial cells in ectodermally derived tissues and is implicated in tumorigenesis of several neoplastic entities. However, the biological and regulatory roles of these isoforms in salivary gland tumorigenesis remain unknown. Our results show a reciprocal expression between TA and DeltaN isoforms in both benign and malignant salivary tumors. The most dominantly expressed were the DeltaN isoforms, whereas the TA isoforms showed generally low levels of expression, except in a few tumors. High DeltaNp63 expression characterized tumors with aggressive behavior, whereas tumors with high TAp63 expression were significantly smaller and less aggressive. In salivary gland cells, high expression of DeltaNp63 led to enhanced cell migration and invasion and suppression of cell senescence independent of TAp63 and/or TP53 gene status. We conclude the following: i) overexpression of DeltaNp63 contributes to salivary tumorigenesis, ii) DeltaNp63 plays a dominant negative effect on the TA isoform in the modulation of cell migration and invasion, and iii) the DeltaN isoform plays an oncogenic role and may represent an attractive target for therapeutic intervention in patients with salivary carcinomas.