The p53 pathway is commonly altered during oral and skin carcinogenesis. The lip is a transition tissue between skin and oral mucosa, which in response to UVB exposure also exhibits alterations in the expression of p53 and p53-related genes that could lead to malignant transformation. To assess if the p53-regulated proteins murine-double-minute (mdm)-2 and p21 are altered during early lip carcinogenesis, biopsies from normal lip (n=16) and the premalignant lip lesion, actinic cheilitis (AC) (n=26) were processed for the immunohistochemical detection of p53, p21 and mdm-2 in serial co-localized sections. Epithelial co-expression of p53 and mdm-2 was significantly increased in AC as compared to normal lip (P<0.001). No differences in epithelial p21 expression were found between normal lip and AC. While in normal lip mdm-2 and p21 were significantly correlated with p53, in AC only mdm-2 was associated with p53 expression. Multivariate logistic regression analysis of the three markers (Wald stepwise) showed that p53 is the only predictor of AC. The results point to alterations in the p53 pathway during early lip carcinogenesis, highlighting p53 as a potential marker of early malignancy of the lip.