The aim of this research was to detect new valid prognostic indicators that allow us to choose the best therapy and follow-up for patients with a poor prognosis, One hundred and twenty-nine patients with invasive squamous carcinoma of the vulva treated at the Gynecology Clinic of the University of Padua between January 1, 1975 and December 31,1999 have been evaluated: Protein p53 and ki-67 were studied by immunohistochemical investigations and their prognostic significance was evaluated. The relation with the classic clinico-pathological prognostic factors was also studied. The results showed a close association between tissue overexpression of the two proteins and clinico-pathological characteristics of the aggressivity of the neoplasm. Moreover, the group of positive p53 patients with a diffuse distribution pattern of ki-67 resulted in having a somewhat shorter survival with respect to the groups with negative p53 and/or a focal pattern. Such negative prognostic significance was confirmed by the results of the multivariate analysis performed with the Cox model which shows that patients with p53 positive values and a diffuse pattern have a higher relative risk of death compared to patients with p53 negative values and focal pattern (p = 0.0001). The statistical significance of the prognostic value of the association of p53 and ki-67 thus seems to give these two factors greater weight with respect to the others we investigated.