Lymphatic metastasis constitutes a critical route of disease dissemination, which limits the prognosis of patients with pancreatic ductal adenocarcinoma (PDAC). As lymphangiogenesis has been implicated in stimulation of lymphatic metastasis by vascular endothelial growth factor‐C (VEGF‐C) and VEGF‐D, we studied the effect of the angioregulatory growth factor angiopoietin‐2 (Ang‐2) on PDAC progression. Ang‐2 was found to be expressed in transformed cells of human PDAC specimens, with corresponding Tie‐2 receptors present on blood and lymphatic endothelium. In vitro in PDAC cells, Ang‐2 was subject to autocrine/paracrine TGF‐β stimulation (2‐fold induction, P= 0.0106) acting on the –61‐ to +476‐bp element of the human Ang‐2 promoter. In turn, Ang‐2 regulated the expression of genes involved in cell motility and tumor suppression. Orthotopic PDAC xenografts with forced expression of Ang‐2, but not Ang‐1, displayed increased blood and lymphatic vessel density, and an enhanced rate of lymphatic metastasis (6.7‐ to 9.1‐fold, P<0.01), which was prevented by sequestration of Ang‐2 via coexpression of soluble Tie‐2. Notably, elevated circulating Ang‐2 in patients with PDAC correlated with the extent of lymphatic metastasis. Furthermore, median survival was reduced from 28.4 to 7.7 mo in patients with circulating Ang‐2 ≥ 75th percentile (P=0.0005). These findings indicate that Ang‐2 participates in the control of lymphatic metastasis, constitutes a noninvasive prognostic biomarker, and may provide an accessible therapeutic target in PDAC.—Schulz, P., Fischer, C., Detjen, K. M., Rieke, S., Hilfenhaus, G., von Marschall, Z., Böhmig, M., Koch, I., Kehrberger, J., Hauff, P., Thierauch, K.‐H., Alves, F., Wiedenmann, B., Scholz, A. Angiopoietin‐2 drives lymphatic metastasis of pancreatic cancer. FASEB J. 25, 3325–3335 (2011). www.fasebj.org