Mesothelin is an emerging marker for cancer diagnosis and target based therapy. In addition to mesothelial malignancies, mesothelin expression in malignancies from the ovary, and more recently from the pancreas has been demonstrated. The purpose of this study is to evaluate the expression of this monoclonal antibody in pancreatic carcinoma, chronic pancreatitis and compare it to the expression of p53 protein. Methods: The authors reviewed 100 cases of pancreatic ductal carcinomas from the files of McMaster University Medical Centre. Representative blocks of tumour and adjacent non-neoplastic pancreas were selected for immunohistochemistry. Immunohistochemistry was performed using mesothelin monoclonal antibody (5132, Nova Castra) and p53 protein (DO-7 Dako). Mesothelin staining of greater than 25% of tumour cells was considered to be strongly positive, less than 1% was considered negative, and the remaining cases were called focally positive. Intensity of staining was semi quantitatively graded on a scale of 1-3 (weak, moderate and strong) Up to 5% of p53 staining was considered negative. Result: Mesothelin staining was seen in 90% of pancreatic ductal carcinomas, of which 78% of cases showed staining in 25% or more of the tumour cells. The staining intensity was, graded as 2 in the majority of the positive cases. Cases of chronic pancreatitis showed only occasional focal positive staining in 5% of cases. The normal pancreatic tissue was negative in all cases. 75% of carcinomas expressed p53 in the range of 10-60%. Less than 2% of chronic pancreatitis cases were positive. Conclusion: We conclude that mesothelin is a useful marker for the diagnosis of pancreatic ductal carcinoma and may be helpful in discriminating cases from chronic pancreatitis. However, p53 showed higher specificity but less sensitivity and the expression can be complementary.