Amorphous silicon (a-Si) electronic portal imaging devices (EPIDs) have typically been calibrated to dose at central axis (CAX). Division of acquired images by the flood-field (FF) image that corrects for pixel sensitivity variation as well as open field energy-dependent off-axis response variation should result in a flat EPID response over the entire matrix for the same field size. While the beam profile can be reintroduced to the image by an additional correction matrix, the CAX EPID response to dose calibration factor is assumed to apply to all pixels in the detector. The aim of this work was to investigate the dose response of the Varian aS500 amorphous silicon detector across the entire detector area. First it was established that the EPID response across the panel became stable (within approximately 0.2%) for MU settings greater than approximately 200 MU. The EPID was then FF calibrated with a high MU setting of approximately 400 for all subsequent experiments. Whole detector images with varying MU settings from 2-500 were then acquired for two dose rates (300 and 600 MU/min) for 6 MV photons for two EPIDs. The FF corrected EPID response was approximately flat or uniform across the detector for greater than 100 MU delivered (within 0.5%). However, the off-axis EPID response was greater than the CAX response for small MU irradiations, giving a raised EPID profile. Up to 5% increase in response at 20 cm off-axis compared to CAX was found for very small MU settings for one EPID, while it was within 2% for the second (newer) EPID. Off-axis response nonuniformities attributed to detector damage were also found for the older EPID. Similar results were obtained with the EPID at 18 MV energy and operating in asynchronous mode (acquisition not synchronized with beam pulses), however the profiles were flatter and more irregular for the small MU irradiations. By moving the detector laterally and repeating the experiments, the increase in response off-axis was found to depend on the pixel position relative to the beam CAX. When the beam was heavily filtered by a phantom the off-axis response variation was reduced markedly to within 0.5% for all MU settings. Independent measurements of off-axis point doses with ion chamber did not show any change in off-axis factor with MUs. Measurements of beam quality (TMR20-10) for MU settings of 2, 5, and 100 at central axis and at 15 cm off-axis could not explain the effect. The response change is unlikely to be significant for clinical IMRT verification with this imaging/acclerator system where MUs are of the order of 100-300, provided the detector does not exhibit radiation damage artifacts.