Percutaneous fine needle aspiration (FNA) is the diagnostic method of choice for patients with a pancreatic mass. A positive cytologic diagnosis allows administration of neoadjuvant therapy in patients with resectable disease and avoids laparotomy in patients with locally advanced or metastatic disease. Ninety patients underwent computed tomographically guided FNA of the pancreas, and the results were compared to the final histologic diagnosis. The initial sensitivity for diagnosis of pancreatic adenocarcinoma was 70%. To improve our diagnostic accuracy, 19 independent cytologic criteria were evaluated for each case. Multivariate logistic-regression analysis identified three major criteria (nuclear crowding and overlapping, nuclear contour irregularity, irregular chromatin distribution) and four minor criteria (nuclear enlargement, single epithelial cells, necrosis, mitoses) as the most important predictors of malignancy. In the presence of two or more major or one major and three minor criteria, the sensitivity and specificity for the diagnosis of pancreatic adenocarcinoma were 100%. Objective application of these criteria improved our diagnostic sensitivity to 90%.