Objective. Proliferative verrucous leukoplakia (PVL), a potentially malignant disorder, often undergoes malignant transformation to oral squamous cell carcinoma. The aim of our study was to document and compare the histologic, immunohistochemical, and clinical features and the survival rates of carcinoma arising in patients with PVL (p-scca) with conventional squamous cell carcinoma (c-scca) in order to determine if p-scca should be categorized as a separate clinical entity. Materials and Methods. A retrospective review of 11 patients with PVL, 38 with p-scca tumors and 49 with c-scca tumors: buccal mucosa (n = 28) and gingiva or palate (n = 21). Immunohistochemistry was performed by using antibodies directed against p16, p53, and ki67. Results. P-scca had lower clinical stage (P = .0001), smaller tumor size (P = .0033), no lymph node metastasis (P = .0002) or distant metastasis (P = .05), and better short term (P = .03), but not long term (P = .12) survival. Microscopically, p-scca tumor thickness was significantly less (P = .0001). P-53 overexpression was more common in p-scca (P = .0043) but not ki67 or p16 overexpression. Conclusions. P-scca, compared with c-scca, presented with significantly better prognostic factors and short-term survival rates and longer duration of disease. Our results suggest that p-scca may represent a distinct entity, which may have practical implications when deciding on treatment. Further studies on a larger cohort of patients are recommended.