BACKGROUND: The objective of this study was to assess how atypical diagnostic category (ADC) is followed up, its outcomes, and the predictors that are associated with subsequent diagnosis of neoplasm/malignancy. METHODS: We reviewed pancreatic endoscopic ultrasound fine-needle aspiration (EUS-FNA) with ADC and compared the rate of detection of neoplasms after a repeat FNA, a biopsy/resection, or a clinical follow-up following ADC. Logistic regression was used to determine the factors associated with the diagnosis of a neoplastic or a malignant lesion following ADC. Predictive probability for each case was calculated on the basis of the significant predictors, and whether it improved diagnostic performance was assessed. RESULTS: Of 3832 cases that received pancreatic EUS-FNAs, 187 (4.9%) were ADC. A total of 93 neoplasms (55%), including 61 carcinomas (36%), were detected after an atypical cytologic diagnosis. Similar rates of detecting neoplasms were observed after repeat FNA or biopsy/resection but higher than after clinical follow-up. The presence of a mass, history of alcohol use, and absence of a history of pancreatitis were significant predictors of a higher rate of diagnosis of neoplasm. Weight loss and bile flow obstruction were more likely to be associated with higher rates of carcinoma. Predictive probability demonstrated a wide range of risk and changed the ambiguous diagnosis to informative in 30% of cases. CONCLUSIONS: ADC of pancreas is associated with a high risk of benign and malignant neoplasms regardless of the method of follow-up. The presences of a mass, alcohol use, and absence of a history of pancreatitis are significant predictors of a diagnosis of neoplasm, whereas weight loss and bile duct obstruction are significant predictors of ductal carcinoma following an ADC. © 2013 American Cancer Society.