Objectives: The majority of pancreatic serous cystic neoplasms (SCNs) are benign. However, these neoplasms can cause symptoms and rarely can be aggressive. Identification of factors associated with symptomatic or aggressive SCNs may aid management decisions. The aim of this study was to identify variables that predict aggressive SCNs. Methods: Prospective pathology database was queried for SCNs that were surgically resected at Johns Hopkins Hospital. Tumors were considered aggressive if they invaded surrounding structures and/or vessels or if they metastasized to lymph nodes or distant organs. The associations of gender, tumor size, and tumor location, with the presence or absence of symptoms and tumor behavior were examined using Fisher's exact test, logistic regression, and multivariate analyses. Results: A total of 257 patients with SCNs underwent surgical resection. Mean tumor diameter was 4.9 cm. Tumor location in the head of pancreas (HOP) was associated with symptoms (odds ratio (OR) 1.87, 95% confidence interval (CI) 1.1-3.3). Computed tomography (CT) predicted the diagnosis of SCN in approximately a quarter of patients. Thirteen tumors (mean 10.5 cm) were considered aggressive. Multivariate analysis showed that tumor diameter (OR 1.53, 95% CI 1.24-1.89) and location of tumor in pancreatic head (OR 10.44, 95% CI 1.73-63.04) were independently associated with aggressive behavior. Conclusions: We describe the largest case series of patients with pathologically proven SCNs. CT performed poorly in preoperative diagnosis of SCNs. Large tumor size and head location predicted aggressive behavior. These factors should be considered in the management of patients with SCN.