Background: Despite the most recent therapeutic achievements, pancreatic ductal adenocarcinoma (PDAC) is characterized by poor prognosis and response to treatments. Among the most investigated prognostic biomarkers, the lymphocyte to monocyte ratio (LMr) is gaining increasing interest in literature, mostly in hematological malignancies, breast cancer, bladder cancer, non-small cell lung cancer, colorectal cancer, and resected pancreatic adenocarcinoma. In these settings, a higher LMr allows identifying a subset of patients with a better prognosis. Our study aimed to evaluate the role of the LMr as a prognostic factor in patients affected by metastatic PDAC and to find a cut-off value able to identify a subset of patients with better prognosis and possibly susceptible to other therapeutic options. Methods: Data from 228 patients were collected retrospectively from 2014 to 2021. 175 from the Department of Medical Oncology of the University Hospital of Cagliari and 53 from the Oncology Clinic - University Hospital of Ospedali Riuniti of Ancona. All patients had metastatic PDAC and blood samples were collected before starting first-line chemotherapy. The cut-off value for LMr was calculated according to the ROC curves at 6, 12, and 18 months. Kaplan-Meier curves were then obtained for the evaluation of survivals. Finally, multivariate analysis was performed, taking into consideration the following prognostic factors: sex, ECOG-PS, NL ratio, metastatic sites, Ca19.9 and LDH. Results: The median age was 68 y.o. (range 39-84 y.o.), 123 (54%) were males. Cut off value obtained for LMR, was 4. 156 (68,4%) patients had an LMr < 4 and 72 (31,6%) patients had an LMR ≥ 4. Patients with a ratio ≥ 4 showed a statistically significant difference in terms of median overall survival compared to patients with a ratio < 4 (23 months versus 11 months, p < 0.0001). First-line median progression-free survival was also different in patients with a value greater than or equal to 4 (11 months versus 6 months, p = 0.005), suggesting a better treatment response in the first group of patients. Finally, multivariate analysis showed that LMR ≥ 4 is an independent prognostic factor for OS (p = 0.0005). Conclusions: The results of our study show that the lymphocyte to monocyte ratio could be an important prognostic factor in patients with metastatic pancreatic ductal adenocarcinoma, although the limitations of a retrospective study should be considered. Furthermore, these findings suggest the active role of the immune response in limiting disease progression, indicating a group of patients who could benefit most from a target or combined immunotherapy treatment.