Simple SummaryLeptin and adiponectin are adipokines involved in the carcinogenesis of gastrointestinal cancers, even though no clear link with pancreatic neuroendocrine neoplasms (PanNENs) has yet been investigated. We aimed to evaluate the possible relationship between leptin, adiponectin, and the leptin–adiponectin ratio, and PanNEN’s grade or stage, including the presence of metastases. We obtained a significantly higher concentration of adiponectin in the control group compared to the study group. The concentration of both adipokines was significantly higher in females than in males. An increased leptin–adiponectin ratio was observed in well-differentiated PanNENs (G1) vs. moderatelydifferentiated PanNENs (G2) and in PanNENs with Ki-67 < 3% vs. Ki-67 ≥ 3%. We identified patients with distal disease as having lower leptin levels and decreased leptin–adiponectin ratio. Thisstudy reveals the importance of adipokines assessment and provides new insights into the mechanisms leading to PanNEN development.AbstractData on the possible connection between circulating adipokines and PanNENs are limited. This novel study aimed to assess the serum levels of leptin and adiponectin and their ratio in patients with PanNENs and to evaluate the possible relationship between them and PanNEN’s grade or stage, including the presence of metastases. The study group consisted of PanNENs (n= 83), and healthy controls (n= 39). Leptin and adiponectin measurement by an ELISA assay was undertaken in the entire cohort. The serum concentration of adiponectin was significantly higher in the control group compared to the study group (p< 0.001). The concentration of leptin and adiponectin was significantly higher in females than in males (p< 0.01). Anincreased leptin–adiponectin ratio was observed in well-differentiated PanNENs (G1) vs. moderatelydifferentiated PanNENs (G2) (p< 0.05). An increased leptin–adiponectin ratio was found in PanNENs with Ki-67 < 3% vs. Ki-67 ≥ 3% (p< 0.05). PanNENs with distal disease presented lower leptin levels (p <0.001) and a decreased leptin–adiponectin ratio (p< 0.01) compared with the localized disease group. Leptin, adiponectin, and the leptin–adiponectin ratio may serve as potential diagnostic, prognostic, and predictive biomarkers for PanNENs. Leptin levels and the leptin–adiponectin ratio may play an important role as predictors of malignancy and metastasis in PanNENs.