The development of synthetic computed tomography (CT) (synCT) derived from magnetic resonance (MR) images supports MR-only treatment planning. We evaluated the accuracy of synCT and synCT-generated digitally reconstructed radiographs (DRRs) relative to CT and determined their performance for image guided radiation therapy (IGRT). Magnetic resonance simulation (MR-SIM) and CT simulation (CT-SIM) images were acquired of an anthropomorphic skull phantom and 12 patient brain cancer cases. SynCTs were generated using fluid attenuation inversion recovery, ultrashort echo time, and Dixon data sets through a voxel-based weighted summation of 5 tissue classifications. The DRRs were generated from the phantom synCT, and geometric fidelity was assessed relative to CT-generated DRRs through bounding box and landmark analysis. An offline retrospective analysis was conducted to register cone beam CTs (n=34) to synCTs and CTs using automated rigid registration in the treatment planning system. Planar MV and KV images (n=37) were rigidly registered to synCT and CT DRRs using an in-house script. Planar and volumetric registration reproducibility was assessed and margin differences were characterized by the van Herk formalism. Bounding box and landmark analysis of phantom synCT DRRs were within 1mm of CT DRRs. Absolute planar registration shift differences ranged from 0.0 to 0.7mm for phantom DRRs on all treatment platforms and from 0.0 to 0.4mm for volumetric registrations. For patient planar registrations, the mean shift differences were 0.4±0.5mm (range, -0.6 to 1.6mm), 0.0±0.5mm (range, -0.9 to 1.2mm), and 0.1±0.3mm (range, -0.7 to 0.6mm) for the superior-inferior (S-I), left-right (L-R), and anterior-posterior (A-P) axes, respectively. The mean shift differences in volumetric registrations were 0.6±0.4mm (range, -0.2 to 1.6mm), 0.2±0.4mm (range, -0.3 to 1.2mm), and 0.2±0.3mm (range, -0.2 to 1.2mm) for the S-I, L-R, and A-P axes, respectively. The CT-SIM and synCT derived margins were <0.3mm different. DRRs generated by synCT were in close agreement with CT-SIM. Planar and volumetric image registrations to synCT-derived targets were comparable with CT for phantom and patients. This validation is the next step toward MR-only planning for the brain.