Pancreatic intraepithelial neoplasia is often associated with pancreatic ductal adenocarcinoma and is presumed to be its precursor. It has been difficult to determine the frequency of these lesions because until recently, there was no consensus regarding the terminology and criteria for their grading. Here we compare the frequency and clinical correlates of pancreatic intraepithelial neoplasia in pancreata involved by ductal adenocarcinoma and in benign ones, using the criteria put forward recently. We evaluated pancreatectomy specimens from 82 patients with ductal adenocarcinoma and 152 patients who underwent pancreatectomy for reasons other than primary malignancy (trauma, pancreatitis, and metastatic tumor to pancreas) for the presence, grade, and number of foci of pancreatic intraepithelial neoplasia. Cases were graded by the highest grade of pancreatic intraepithelial neoplasia focus identified. An average of 5.3 sections of pancreas was available for evaluation (range, 1-28 sections). Overall, the frequency of pancreatic intraepithelial neoplasia lesions in ductal adenocarcinoma patients, including Grade 1A (mucinous duct lesions), was 82%, which was significantly higher than the one in benign pancreata -54%, P <.001. There was a progressive increase from normal pancreata to pancreatitis and to ductal adenocarcinoma in the frequency of overall pancreatic intraepithelial neoplasia lesions (16%, 60%, and 82%, respectively) and Grade 3 pancreatic intraepithelial neoplasia (0%, 4%, and 40%, respectively). In most instances, in any given case of higher-grade pancreatic intraepithelial neoplasia lesion, there were also several foci of lower grade lesions. The frequency of higher-grade pancreatic intraepithelial neoplasia lesions (2 and 3) in pancreata resected for ductal adenocarcinoma was 59%, significantly higher than in those without primary carcinoma (17%). This progressive increase in frequency of pancreatic intraepithelial neoplasia from incidental pancreatectomies (presumed to have a nonpathologic pancreas) to pancreatitis (considered a risk factor for carcinoma) and to ductal adenocarcinoma constitutes an indirect support for the precancerous role attributed to pancreatic intraepithelial neoplasia lesions. The relatively high absolute occurrence of pancreatic intraepithelial neoplasia Grade 1A (mucinous duct lesions) in benign conditions (43%) suggests that this group represents a combination of neoplastic and non-neoplastic lesions.