Abstract: Given the established role of matrix metalloproteinases (MMPs) in physiological processes in the skin, we investigated the expression of MMP-2, MMP-9, and MMP-14 to evaluate their role in the grading and development of atypical epithelial lesions. Immunohistochemistry was performed using antibodies against these MMPs in actinic keratosis (AK; n = 24), squamous cell carcinoma (SCC) in situ (SCCIS; n = 27), SCC well differentiated (SCCWD; n = 28), and SCC moderately to poorly differentiated (SCCMPD; n = 20). Tumoral and stromal expression was assessed by intensity (SI) and percentage positivity (PC). The mean of the total score, calculated by adding intensity and percentage positivity, was used for statistical analyses. In AK, SCCIS, SCCWD, and SCCMPD, mean tumoral MMP-2 expression was 3.33, 4.07, 4.46, and 3.40, respectively (P = NS for all) and stromal expression was 1.42, 3.26, 3.07, and 1.55 respectively (P < 0.05 for AK vs. SCCIS/SCCWD and SCCMPD vs. SCCIS/SCCWD); mean tumoral MMP-9 expression was 4.33, 4.11, 4.46, and 3.35, respectively, and stromal expression was 4.29, 4.41, 4.75, and 4.60, respectively (P = NS for all) and, mean tumoral MMP-14 expression was 1.58, 2.41, 0.32, and 0.35, respectively (P < 0.05 AK vs. SCCWD and SCCIS vs. SCCWD/SCCMPD) and stromal expression was 3.04, 3.52, 0.46, and 0.60, respectively (P < 0.05 for AK vs. SCCWD/SCCMPD). Only MMP-14 showed a statistically significant linear trend with decreasing values for tumoral and stromal expression with invasion suggesting that it might be of use as a prognosticator. Enhanced stromal MMP-2 expression in SCCIS and SCCWD relative to AK suggests that it may be of relevance to disease progression.