Grading of oral epithelial dysplasia (OED) can be challenging with considerable intra- and inter-observer variability. Abnormal immunohistochemical staining patterns of the tumor suppressor protein, p53, have been recently shown to be potentially associated with progression in OED. We retrospectively identified 214 oral biopsies from 203 patients recruited in a longitudinal study between 2001 and 2008 with diagnosis of reactive, non-dysplastic lesions, low-grade lesions (LGLs; mild OED, moderate OED) and high-grade lesions (HGLs; severe OED /carcinoma in situ). Tissue microarrays (TMA) were constructed from the most representative area of the pathology. Three consecutive sections were sectioned and stained for hematoxylin and eosin, p53 immunohistochemistry, and p16 immunohistochemistry. The staining results were reviewed by two pathologists blinded to clinical outcome. Samples were categorized into p53-abnormal OED (n = 46), p53-conventional OED (n = 118), and p53-HPV (HPV-associated) OED (n = 12) using a previously published pattern-based approach. All cases of p53-HPV (HPV-associated) OED were identified in HGLs. In contrast, cases of p53-abnormal OED were observed in mild OED (9.5%), moderate OED (23%), and severe OED /carcinoma in situ (51%). None of the 27 reactive or non-dysplastic lesions showed abnormal p53 staining patterns. Among the 135 LGLs, 23 cases (17.0%; 2 mild OED and 21 moderate OED) progressed to HGL or squamous cell carcinoma, with 11 cases showing progression within the first 3 years. Remarkably, 82% (9/11) of these faster-progressors showed abnormal p53 patterns. Survival analysis revealed that p53-abnormal OED had significantly poorer progression-free probability (p<0.0001) with hazard ratio of 11.24 (95%CI, 4.26-29.66), compared to p53-conventional OED. Furthermore, p53-abnormal OED had poorer local-recurrence-free survival compared to p53 wild-type OED (p = 0.03). The study supports that OED with p53-abnormal pattern is at high-risk for progression and recurrence, independent of the dysplasia grade.