The objective of this study was to evaluate extracellular matrix metalloproteinase (EMMPRIN) as a novel target in orthotopic pancreatic cancer murine models. MIA PaCa-2 human pancreatic tumor cells were implanted in groups 1 and 3–7, whereas MIA PaCa-2 EMMPRIN knockdown cells were implanted in group 2. Dosing with anti-EMMPRIN antibody started immediately after implantation for groups 1–3 (residual tumor model) and at 21 days after cell implantation for groups 4–7 (established tumor model). Groups 3, 5, and 7 were treated with anti-EMMRPIN antibody (0.2–1.0 mg) twice weekly for 2–3 weeks, whereas the other groups served as the control. In the residual tumor model, tumor growth of anti-EMMPRIN-treated group was successfully arrested for 21 days (15±4 mm3), which was significantly lower than that of the EMMPRIN knockdown group (80±15 mm3; P=0.001) or the control group (240±41 mm3; P<0.001). In the established tumor model, anti-EMMPRIN therapy lowered tumor volume increase by approximately 40% compared with the control, regardless of the dose amount. Ki67-expressed cell density of group 5 was 939±150 mm−2, which was significantly lower than that of group 4 (1709±145 mm−2; P=0.006). Microvessel density of group 5 (30±6 mm−2) was also significantly lower than that of group 4 (53±5 mm−2; P=0.014), whereas the microvessel size of group 5 (191±22 μm2) was significantly larger than that of group 4 (113±26 μm2; P=0.049). These data show the high potential of anti-EMMPRIN therapy for pancreatic cancer and support its clinical translation.