Mannan-binding lectin-associated serine protease-2 (MASP-2) is a serine protease involved in the activation of lectin complement pathway. The differential expression of MASP-2 in human esophageal squamous cell carcinoma (ESCC) was recently reported from our laboratory using differential display. To determine the expression of MASP-2 protein, we raised a polyclonal antibody to human MASP-2 and used it for immunohistochemical analysis of MASP-2 in ESCCs. The antibody showed a single band of predicted molecular weight by western blotting. In normal human liver tissue, the cytoplasm was distinctly labeled by the antibody. Intriguingly, besides the cytoplasm, the nuclei of esophageal tumor cells were also labeled. To investigate the association of MASP-2 expression with esophageal tumorigenesis, its expression was analyzed in 51 primary ESCCs, 32 dysplasias, 21 histologically normal esophageal tissues and 6 adenocarcinomas by immunohistochemistry. Increased MASP-2 expression was observed in ESCCs (p = 0.001, Odd's ratio (OR) = 3.662) and in premalignant condition, dysplasia (p = 0.000, OR = 5.091) in comparison with the normal tissues. MASP-2 expression in ESCCs was associated with late clinical stage (p = 0.009, O.R. = 3.430) and nodal metastasis (p = 0.001, O.R. = 4.520). In conclusion, our antibody was demonstrated to be useful in recognizing MASP-2 expression on paraffin embedded tissue sections. To our knowledge, this is the first report showing MASP-2 expression in a solid tumor. MASP-2 expression in premalignant stage (dysplasia) as well as in ESCCs and its association with late clinical stage and nodal metastasis suggest that alteration in its expression is maintained during disease progression and is associated with aggressive tumor behavior. © 2006 Wiley-Liss, Inc.