The aim of this work was to experimentally determine the difference in response of an amorphous silicon (a-Si) electronic portal imaging device (EPID) to the open and multileaf collimator (MLC) transmitted beam components of intensity modulated radiation therapy (IMRT) beams. EPID dose response curves were measured for open and MLC transmitted (MLCtr) 10×10 cm2 beams at central axis and with off axis distance using a shifting field technique. The EPID signal was obtained by replacing the flood-field correction with a pixel sensitivity variation matrix correction. This signal, which includes energy-dependent response, was then compared to ion-chamber measurements. An EPID calibration method to remove the effect of beam energy variations on EPID response was developed for IMRT beams. This method uses the component of open and MLCtr fluence to an EPID pixel calculated from the MLC delivery file and applies separate radially dependent calibration factors for each component. The calibration procedure does not correct for scatter differences between ion chamber in water measurements and EPID response; these must be accounted for separately with a kernel-based approach or similar method. The EPID response at central axis for the open beam was found to be 1.28±0.03 of the response for the MLCtr beam, with the ratio increasing to 1.39 at 12.5 cm off axis. The EPID response to MLCtr radiation did not change with off-axis distance. Filtering the beam with copper plates to reduce the beam energy difference between open and MLCtr beams was investigated; however, these were not effective at reducing EPID response differences. The change in EPID response for uniform sliding window IMRT beams with MLCtr dose components from 0.3% to 69% was predicted to within 2.3% using the separate EPID response calibration factors for each dose component. A clinical IMRT image calibrated with this method differed by nearly 30% in high MLCtr regions from an image calibrated with an open beam calibration factor only. Accounting for the difference in EPID response to open and MLCtr radiation should improve IMRT dosimetry with a-Si EPIDs. © 2007 American Association of Physicists in Medicine.