Background and Aims <p>Studies comparing the diagnostic efficacy of histology combined with smear cytology (SC) and liquid-based cytology (LBC) in endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of solid pancreatic lesions are limited, mainly due to the ongoing debate about the need for simultaneous use of SC and LBC as adjuncts to histology. We aimed to evaluate the diagnostic efficacy of combining histology with single cytology in EUS-FNA of solid pancreatic lesions.</p> Methods <p>We retrospectively searched hospital database from January 2021 to December 2023 to identify patients who underwent EUS-FNA with concomitant histology, SC and LBC. The diagnostic accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and area under curve (AUC) of the above methods were compared. The primary endpoint was the diagnostic efficacy of each method, with the final diagnosis confirmed by surgical pathology, or clinical follow-up.</p> Results <p>Of the 293 patients included, 236 were malignant and 57 were benign. Histology alone demonstrated a higher diagnostic performance than either SC or LBC. Combining histology with either SC or LBC improved sensitivity, but reduced specificity. No significant increase in diagnostic efficacy was observed when combining histology with both cytological methods. Additionally, SC with more than 8 smears showed higher sensitivity and accuracy than LBC.</p> Conclusions <p>EUS-FNA histology only requires combination with one cytological method (either SC or LBC), rather than both methods, to improve diagnostic accuracy for solid pancreatic lesions, meet clinical diagnostic requirements, and achieve high cost-effectiveness.</p>