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A system for cone-beam computed tomography (CBCT) based on a flat-panel imager (FPI) is used to examine the magnitude and effects of x-ray scatter in FPI-CBCT volume reconstructions. The system is being developed for application in image-guided therapies and has previously demonstrated spatial resolution and soft-tissue visibility comparable or superior to a conventional CT scanner under conditions of low x-ray scatter. For larger objects consistent with imaging of human anatomy (e.g., the pelvis) and for increased cone angle (i.e., larger volumetric reconstructions), however, the effects of x-ray scatter become significant. The magnitude of x-ray scatter with which the FPI-CBCT system must contend is quantified in terms of the scatter-to-primary energy fluence ratio (SPR) and scatter intensity profiles in the detector plane, each measured as a function of object size and cone angle. For large objects and cone angles (e.g., a pelvis imaged with a cone angle of 6°), SPR in excess of 100% is observed. Associated with such levels of x-ray scatter are cup and streak artifacts as well as reduced accuracy in reconstruction values, quantified herein across a range of SPR consistent with the clinical setting. The effect of x-ray scatter on the contrast, noise, and contrast-to-noise ratio (CNR) in FPI-CBCT reconstructions was measured as a function of SPR and compared to predictions of a simple analytical model. The results quantify the degree to which elevated SPR degrades the CNR. For example, FPI-CBCT images of a breast-equivalent insert in water were degraded in CNR by nearly a factor of 2 for SPR ranging from ~2% to 120%. The analytical model for CNR provides a quantitative understanding of the relationship between CNR, dose, and spatial resolution and allows knowledgeable selection of the acquisition and reconstruction parameters that, for a given SPR, are required to restore the CNR to values achieved under conditions of low x-ray scatter. For example, for SPR=100%, the CNR in FPI-CBCT images can be fully restored by: (1) increasing the dose by a factor of 4 (at full spatial resolution); (2) increasing dose and slice thickness by a factor of 2; or (3) increasing slice thickness by a factor of 4 (with no increase in dose). Other reconstruction parameters, such as transaxial resolution length and reconstruction filter, can be similarly adjusted to achieve CNR equal to that obtained in the scatter-free case. ©2001 American Association of Physicists in Medicine.