Macrophages play a critical role in the initiation and progression in various human solid tumors; however, their role and transformation in pancreatic ductal adenocarcinoma (PDAC) were still illusive. Here, immunohistochemistry was used to determine CD206 (specific marker of M2 macrophage) and PKM2 expression in PDAC tissues. Statistical analysis, such as Pearson χ2 test, Spearman's rank test, Kaplan-Meier and COX regression assay were used to evaluate their roles on PDAC prognosis. Data showed that both CD206 and PKM2 were elevated and responsible for a poor prognosis for PDAC. In addition, we showed that the two factors were positively correlated; co-overexpression of the two factors conferred the worst prognosis and functioned as an independent prognostic factor for the disease. Our data showed that M2 macrophage infiltration was correlated with PKM2 expression in PDAC cells. The two markers exerted synergistic effect on PDAC progression. Our results suggested dual-target inhibition M2 macrophage polarization and PKM2 expression of cancer cells might be novel approaches to treat PDAC.