Endoscopic ultrasound fine needle aspiration (EUS-FNA) cytology from an intracystic fluid is useful in the differentiation of pancreatic cysts, with low sensitivity, which increases when the solid component is targeted. The clinical utility of contrast-enhanced guided EUS-FNA (CH-EUS-FNA) in the solid component is not known. We aimed to assess the diagnostic value of CH-EUS-FNA in enhanced mural nodules and discrimination between different cysts using contrast-enhanced endoscopic ultrasound (CH-EUS). The prospective study recruited patients with pancreatic cysts with an unclear diagnosis. The CH-EUS was followed by CH-EUS-FNA. The final diagnosis was based on surgery or the correlation between clinical history, cross-sectional imaging, echoendoscopic morphology, cystic fluid analysis, and follow-up. Fifty-eight patients with pancreatic cysts were evaluated. The mucinous cysts had wall arterial enhancement more often than non- mucinous cysts (p < 0.0001), with 90.2% sensitivity and 70.6% specificity. The CH-EUS-FNA from cystic fluid and mural nodules identified mucinous cysts and malignancy with 82.4% and 84.2% sensitivity and 92% and 100% specificity. Twenty-one cysts had solid components, but only 13 were enhanced mural nodules on EUS assessment with conclusive cytology in all cases and malignancy in 76.9%. Contrast-enhanced endoscopic ultrasound should be completed in all PCN with solid components in order to avoid unnecessary EUS-FNA and to guide FNA for the identification of malignant cysts.