Electronic portal imaging devices (EPIDs) based on active matrix, flat-panel imagers (AMFPIs) have been widely used for patient set-up verification in radiotherapy, and are being investigated for megavoltage (MV) cone-beam computed tomography (CBCT). However, the performance of conventional AMFPI-based EPIDs is limited by their relatively low detective quantum efficiency (DQE) at radiotherapy energies, ~1% for 6 MV X rays. Consequently, MV CBCT carried out with these inefficient EPIDs requires impractically high doses to achieve soft-tissue visualization. In order to significantly improve DQE, this research work examined thick mercuric iodide (HgI2) photoconductors in the form of particle in binder (PIB) and thick, segmented scintillators consisting of 2D matrices of scintillating crystals separated by septal walls. Through simulation of radiation transport, quantum efficiency (QE), modulation transfer function (MTF) and DQE were studied as a function of the thickness of PIB-HgI2 photoconductors. Simulations of radiation and optical transport were carried out to investigate how various geometric and optical properties affect the DQE for segmented CsI:Tl and BGO scintillators. Four prototype EPIDs, employing three CsI:Tl scintillators (11.4, 25.6 and 40.0 mm thick) and one BGO scintillator (11.3 mm thick), were evaluated using a 6 MV photon beam. Finally, the potential MV CBCT performance provided by segmented scintillators was investigated by simulation of radiation transport. Compared to conventional EPIDs, PIB-HgI2 photoconductors up to 6 mm thick have the potential to provide up to a factor of ~5 improvement in DQE. Segmented CsI:Tl and BGO scintillators up to 40 mm thick can provide DQE improvement of up to a factor of ~29 and 42, respectively, through optimization of optical properties. The three CsI:Tl prototypes demonstrated DQE improvement of up to a factor of ~25 at low spatial frequencies, while the BGO prototype exhibited an improvement of a factor of ~20 at zero frequency and over a factor of ~10 at the Nyquist frequency. The simulation results indicate that CsI:Tl and BGO scintillators up to 40 mm thick can provide dose reduction for MV CBCT of up to a factor of ~51 and 59, respectively, creating the possibility of providing soft-tissue visualization at clinically acceptable doses. Advisors/Committee Members: Antonuk, Larry E. (committee member), Rogers, W. Leslie (committee member), Clarke, Roy (committee member), Clinthorne, Neal H. (committee member).