Objectives: The objective of this study was to determine whether alterations in the expression of p53, caspase-3 Bcl-2, and ki-67 appear early in premalignant oral epithelium and show clonal behavior. Study Design: Samples from 41 tumors with their adjacent non-tumor epithelia were immunohistochemically analyzed using monoclonal antibodies that recognize p53, caspase-3, Bcl-2, and Ki-67 Results: A statistically significant association was found between the expression in tumor and adjacent epithelium of p53, caspase-3, and Bcl-2 but not of k-67. A significant association was observed between the expression of ki-67 and p53 in both localizations. In non-tumor (premalignant) epithelium samples, there was a significant inverse relationship between the expressions of p53 and caspase-3 and a significant direct relationship between the expressions of p53 and Bcl-2. Conclusions: Alterations in these proteins appear to operate in combination with premalignant epithelia to create hyperproliferative cell states that favor the acquisition of summative oncogenic errors that confer invasive capacity.