Background and purpose: Pancreatic radiotherapy (RT) is limited by uncertain target motion. We quantified 3D patient/organ motion during pancreatic RT and calculated required treatment margins. Materials and methods: Cone-beam computed tomography (CBCT) and orthogonal fluoroscopy images were acquired post-RT delivery from 13 patients with locally advanced pancreatic cancer. Bony setup errors were calculated from CBCT. Inter- and intra-fraction fiducial (clip/seed/stent) motion was determined from CBCT projections and orthogonal fluoroscopy. Results: Using an off-line CBCT correction protocol, systematic (random) setup errors were 2.4 (3.2), 2.0 (1.7) and 3.2 (3.6) mm laterally (left-right), vertically (anterior-posterior) and longitudinally (cranio-caudal), respectively. Fiducial motion varied substantially. Random inter-fractional changes in mean fiducial position were 2.0, 1.6 and 2.6 mm; 95% of intra-fractional peak-to-peak fiducial motion was up to 6.7, 10.1 and 20.6 mm, respectively. Calculated clinical to planning target volume (CTV-PTV) margins were 1.4 cm laterally, 1.4 cm vertically and 3.0 cm longitudinally for 3D conformal RT, reduced to 0.9, 1.0 and 1.8 cm, respectively, if using 4D planning and online setup correction. Conclusions: Commonly used CTV-PTV margins may inadequately account for target motion during pancreatic RT. Our results indicate better immobilisation, individualised allowance for respiratory motion, online setup error correction and 4D planning would improve targeting. © 2012 Elsevier Ireland Ltd. All rights reserved.