Regenerating gene (REG) Iα is not only overexpressed in a subset of gastric cancers, but also involved in tumor progression. However, the mechanism by which (REG) Iα promotes tumor growth is not fully understood. In the present study, we investigated whether REG Iα plays a role in angiogenesis during the progression of gastric cancers. Expression of REG Iα and its receptor (EXTL3; exostoses like-3) was examined using immunohistochemistry in specimens of human gastric cancer. Microvessel density (MVD) in gastric cancer tissues was evaluated using an image analysis system after CD34 immunostaining. Relationships among clinicopathological features, REG Iα expression and MVD in gastric cancer tissues were analyzed. Effects of REG Iα protein on HUVEC cells in terms of proliferation and anti-apoptosis were assessed by WST-1 assay and FACS, respectively. Furthermore, the intracellular signaling by which REG Iα exerts its biological roles was examined in vitro. REG Iα expression was significantly related to lymph node metastasis and its receptor EXTL3 was ubiquitously expressed in not only the tumor cells, but also the tumor vessel cells in the gastric cancer tissues. MVD was significantly higher in gastric cancers that were REG Iα-positive than in those that were negative. Treatment with REG Iα protein promoted growth and anti-apoptosis through activation of the ERK and Akt signaling pathways in HUVEC cells, whereas these effects were attenuated by treatment with anti-REG Iα -antibody. REG Iα protein may play a role in angiogenesis during progression of gastric cancer.