Abstract Purpose: The risk of malignant transformation of oral preneoplastic lesion (OPL) is difficult to assess. ΔNp63 is an early oncoprotein associated with mucosal tumorigenesis. The purpose of this study was to assess ΔNp63 expression in OPL and its role as a marker of oral cancer risk. Experimental Design: ΔNp63 expression was determined using immunohistochemistry in 152 OPL patients included in a clinical trial comparing retinyl palmitate alone or plus β-carotene with low-dose 13-cis-retinoic acid. The associations between ΔNp63 expression as well as ΔNp63 expression with other potential risk factors for oral cancer development were analyzed. Results: ΔNp63 expression was positive in 41 (27%) patients, clusters of intraepithelial inflammatory cells (EIC) were noted in 37 (26%) patients, and podoplanin (previously reported) was positive in 56 (37%) patients. Significantly more patients whose lesions were ΔNp63 positive or exhibited EIC developed oral cancers. In the multicovariate analysis including age, treatment, and histologic status as cofactors, positive ΔNp63 expression was associated with an increased hazard ratio of 3.308 (95% confidence interval, 1.663-6.580; P = 0.0007). Patients whose lesions showed positive ΔNp63, podoplanin, and EIC had the highest oral cancer risk with a hazard ratio of 4.372 (95% confidence interval, 1.912-9.992; P = 0.0005) and 61% oral cancer development rate at 5 years compared with 15% of other OPL patients (P < 0.0001). Conclusion: ΔNp63 overepression in OPL is associated with increased oral cancer risk. Together, ΔNp63, podoplanin, and EIC may be used as biomarkers to identify OPL patients with substantially high oral cancer risk. (Clin Cancer Res 2009;15(19):6284–91)