Fractionated stereotactic radiotherapy (SRT) requires accurate and reproducible immobilization of the patient's head. This randomized study compared the efficacy of two commonly used forms of immobilization used for SRT. Two routinely used methods of immobilization, which differ in their approach to reproduce the head position from day to day, are the Gill-Thomas-Cosman (GTC) frame and the BrainLab thermoplastic mask. The GTC frame fixates on the patient's upper dentition and thus is in direct mechanical contact with the cranium. The BrainLab mask is a two-part masking system custom fitted to the front and back of the patient's head. After patients signed an IRB-approved informed consent form, eligible patients were randomized to either GTC frame or mask for their course of SRT. Patients were treated as per standard procedure; however, prior to each treatment a set of digital kilovolt images (ExacTrac, BrainLabAB, Germany) was taken. These images were fused with reference digitally reconstructed radiographs obtained from treatment planning CT to yield lateral, longitudinal, and vertical deviations of isocenter and head rotations about respective axes. The primary end point of the study was to compare the two systems with respect to mean and standard deviations using the distance to isocenter measure. A total of 84 patients were enrolled (69 patients evaluable with detailed positioning data). A mixed-effect linear regression and two-tiled t test were used to compare the distance measure for both the systems. There was a statistically significant (p < 0.001) difference between mean distances for these systems, suggesting that the GTC frame was more accurate. The mean 3D displacement and standard deviations were 3.17+1.95 mm for mask and 2.00+1.04 mm for frame. Both immobilization techniques were highly effective, but the GTC frame was more accurate. To optimize the accuracy of SRT, daily kilovolt image guidance is recommended with either immobilization system.