To develop a quality assurance (QA) of XVI cone beam system (XVIcbs) for its optimal imaging-guided radiotherapy (IGRT) implementation, and to construe prostate tumor margin required for intensity-modulated radiation therapy (IMRT) if IGRT is unavailable. XVIcbs spatial accuracy was explored with a humanoid phantom; isodose conformity to lesion target with a rice phantom housing a soap as target; image resolution with a diagnostic phantom; and exposure validation with a Radcal ion chamber. To optimize XVIcbs, rotation flexmap on coincidency between gantry rotational axis and that of XVI cone beam scan was investigated. Theoretic correlation to image quality of XVIcbs rotational axis stability was elaborately studied. Comprehensive QA of IGRT using XVIcbs has initially been explored and then implemented on our general IMRT treatments, and on special IMRT radiotherapies such as head and neck (H and N), stereotactic radiation therapy (SRT), stereotactic radiosurgery (SRS), and stereotactic body radiotherapy (SBRT). Fifteen examples of prostate setup accounted for 350 IGRT cone beam system were analyzed. IGRT accuracy results were in agreement ± 1 mm. Flexmap 0.25 mm met the manufacturer's specification. Films confirmed isodose coincidence with target (soap) via XVIcbs, otherwise not. Superficial doses were measured from 7.2-2.5 cGy for anatomic diameters 15-33 cm, respectively. Image quality was susceptible to rotational stability or patient movement. IGRT using XVIcbs on general IMRT treatments such as prostate, SRT, SRS, and SBRT for setup accuracy were verified; and subsequently coordinate shifts corrections were recorded. The 350 prostate IGRT coordinate shifts modeled to Gaussian distributions show central peaks deviated off the isocenter by 0.6 ± 3.0 mm, 0.5 ± 4.5 mm in the X(RL)- and Z(SI)-coordinates, respectively; and 2.0 ± 3.0 mm in the Y(AP)-coordinate as a result of belly and bladder capacity variations. Sixty-eight percent of confidence was within ± 4.5 mm coordinates shifting. IGRT using XVIcbs is critical to IMRT for prostate and H and N, especially SRT, SRS, and SBRT. To optimize this modality of IGRT, a vigilant QA program is indispensable. Prostate IGRT reveals treatment accuracy as subject to coordinates' adjustments; otherwise a 4.5-mm margin is required to allow for full dose coverage of the clinical target volume, notwithstanding toxicity to normal tissues.