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Early pancreatic cancer response following cetuximab and/or irinotecan therapies was measured by serial dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) before and during therapy. Groups 1 to 4 ( n = 6/group) of SCID mice bearing orthotopic pancreatic adenocarcinoma xenografts expressing luciferase were treated with phosphate-buffered saline, cetuximab, irinotecan, or cetuximab combined with irinotecan, respectively, twice weekly for 3 weeks. DCE-MRI was performed on days 0, 1, 2, and 3 after therapy initiation, whereas anatomic magnetic resonance imaging was performed on days 0, 1, 2, 3, 6, and 13. Bioluminescence imaging was performed on days 0 and 21. At day 21, all tumors were collected for further histologic analyses (Ki-67 and CD31 staining), whereas tumor dimensions were measured by calipers. The K trans values in the 0.5 mm–thick peripheral tumor region were calculated, and the changes in K trans during the 3 days posttherapy were compared to tumor volume changes, bioluminescent signal changes, and histologic findings. The K trans changes in the peripheral tumor region after 3 days of therapy were linearly correlated with 21-day decreases in tumor volume ( p < .001), bioluminescent signal ( p = .050), microvessel densities ( p = .002), and proliferating cell densities ( p = .001). This study supports the clinical use of DCE-MRI for pancreatic cancer patients for early assessment of an anti–epidermal growth factor receptor therapy combined with chemotherapy.