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Salivary malignancies are rare, heterogeneous, unpredictable in their clinical behavior and seldom studied. This study focused on examining the expression of mutated p53, the most prevalent mutated gene related to human cancer, in a rather large cohort of salivary malignancies (n = 70) and for a prolonged period (20 years). P53 was found to be a most powerful predictor for poor survival and more so when the tumor concurrently expressed TUNEL and heparanase markers, dramatically dropping the survival probability of the patients to 0! Survival probability at 6 years for patients with tumors stained negatively vs. positively for p53, TUNEL and heparanase was 100% vs. 49% while at 18 years this probability dropped to 67% vs. 0%, respectively (p = 0.023). Significant correlation rates were found between age and poor survival, age and p53, and p53 and other co-existing malignancies. These findings support mutated p53 as a prognostic predictor and a pivotal player in salivary carcinogenesis. Significantly more extensive therapy applied to salivary p53-positive patients did not improve mortality rate, questioning the justification for such extensive therapy and emphasizing the need to understand p53, TUNEL and heparanase biological pathways and develop additional therapeutic tools for fighting salivary cancer.