Purpose: The objective of this study is to evaluate the therapeutic response to a novel monoclonal antibody targeting human extracellularmatrixmetalloproteinase inducer (EMMPRIN) in combination with gemcitabine in a pancreatic-tumor xenograftmurinemodel by sequential 2-deoxy-2-[18F]fluoro-D-glucose ( 18F-FDG) positron emission tomography/computed tomgraphy (PET/CT) imaging. Procedures: Four groups of SCID mice bearing orthotopic pancreatic tumor xenografts were injected with phosphate-buffered saline, gemcitabine (120 mg/kg BW), anti-EMMPRIN antibody (0.2 mg), or combination, respectively, twice weekly for 2 weeks, while 18F-FDG PET/CT imaging was performed weekly for 3 weeks. Changes in mean standardized uptake value (SUV mean) of 18F-FDG and volume of tumors were determined. Results: The tumor SUV mean change in the group receiving combination therapy was significantly lower than those of the other groups. Tumor-volume changes of groups treated with anti-EMMPRIN monotherapy or combined therapy were significantly lower than that of the control group. Conclusions: These data provide support for clinical studies of anti-EMMPRIN therapy with gemcitabine for pancreatic cancer treatment. © Academy of Molecular Imaging and Society for Molecular Imaging, 2011.