Cystic tumors of the pancreas form a heterogeneous group, with benign, premalignant, and malignant tumors. The molecular events that underlie their neoplastic transformation process are poorly understood. Our purpose was to study DNA ploidy by flow cytometry and p53 protein expression by immunohistochemistry in a large series of cystic tumors of the pancreas. The series of 51 surgical specimens included 18 serous cystadenomas, 20 mucinous cystic tumors (benign, n = 14; borderline, n = 1; malignant, n = 5), 10 intraductal papillary-mucinous tumors (benign, n = 4; borderline, n = 1; malignant, n = 5), and 3 papillary and cystic tumors. The p53 protein immunohistochemical study was done in all cases on deparaffinized sections stained with the monoclonal antibody DO7. DNA flow cytometry was performed in 31 cases on formalin-fixed and paraffinembedded material. Neither p53 protein immunoreactivity nor DNA aneuploidy was observed in any case of serous cystadenoma. p53 protein overexpression was present in four of five malignant mucinous cystic tumors but was absent in benign and borderline cases. Only one case of malignant mucinous cystic tumor was DNA aneuploid. All benign and borderline intraductal papillary-mucinous tumors were p53 negative, and two of five malignant cases were p53 positive. There was no DNA aneuploidy in any case of intraductal papillary-mucinous tumors. The three cases of papillary-cystic tumors showed neither p53 protein immunoreactivity nor DNA aneuploidy. In cystic tumors of the pancreas, p53 protein overexpression and DNA aneuploidy are rare events, restricted to malignant cases, mostly mucinous cystadenocarcinomas. Our results confirm that this group of tumors is heterogeneous and underline the need for earlier markers of an aggressive behavior.