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Background & Objective: Pancreatobiliary system disorders commonly include inflammatory diseases and tumors. Diagnosis of pancreatic cancer is challenging and is mostly achieved when the disease has extensively progressed, and metastasis has occurred. Therefore, this study was performed to evaluate cytopathology in the diagnosis of Pancreatobiliary malignancies, which can improve diagnostic adequacy and accuracy., Methods: A total of 116 cytopathologic results of the Pancreatobiliary system, performed in the Pathology Department of Taleghani Hospital, Tehran, Iran during 2017-2018 were selected and examined in this observational study. The frequency of different results was determined and compared with other variables., Results: The most common location of the lesions was the pancreas (47%). The lesions were categorized as malignant, benign, negative, suspicious for malignancy (SFM), and atypical in 28%, 10%, 24%, 14%, and 9% of the cases, respectively. In other cases, lesions were considered non-diagnostic. Rapid on-site evaluation (ROSE) was conducted in 25% of patients. Compatibility of the initial and final diagnoses was 100%, 50%, and 60% in cases with "malignant", "benign", and "negative" diagnoses, respectively. The sensitivity, specificity, as well as positive and negative predictive values of cytopathology in the diagnosis of Pancreatobiliary lesions were 75.8%, 92.3%, 95.9%, and 61.5%, respectively., Conclusion: Our findings indicated that half of the lesions of the Pancreatobiliary system were positive, SFM, and atypical. Fine-needle aspiration (FNA) and endoscopic ultrasound-guided FNA (EUS-FNA) were effective modalities in diagnosing Pancreatobiliary malignancies. The most important point in our experience is the increase in diagnostic sensitivity in the presence of ROSE. Therefore, the simultaneous use of ROSE and EUS-FNA can reduce the need for re-sampling., Competing Interests: The authors declared that there is no conflict of interest regarding the publication of this article.