The purpose of this study was to evaluate the accuracy of a two-dimensional (2D) to three-dimensional (3D) image-fusion-guided target localization system and a mask based stereotactic system for fractionated stereotactic radiotherapy (FSRT) of cranial lesions. A commercial x-ray image guidance system originally developed for extracranial radiosurgery was used for FSRT of cranial lesions. The localization accuracy was quantitatively evaluated with an anthropomorphic head phantom implanted with eight small radiopaque markers (BBs) in different locations. The accuracy and its clinical reliability were also qualitatively evaluated for a total of 127 fractions in 12 patients with both kV x-ray images and MV portal films. The image-guided system was then used as a standard to evaluate the overall uncertainty and reproducibility of the head mask based stereotactic system in these patients. The phantom study demonstrated that the maximal random error of the image-guided target localization was in each direction in terms of the 95% confidence interval (CI). The systematic error varied with measurement methods. It was approximately , mainly in the longitudinal direction, for the kV x-ray method. There was a systematic difference, primarily in the lateral direction, between the kV x-ray and the MV portal methods. The patient study suggested that the accuracy of the image-guided system in patients was comparable to that in the phantom. The overall uncertainty of the mask system was , and the reproducibility was in terms of 95% CI. The study demonstrated that the image guidance system provides accurate and precise target positioning.