OBJECT: The goal of this study was to develop a technique for performing submillimeter high-precision volume-staged Gamma Knife surgery and investigate its potential benefits in comparison with hypofractionated stereotactic radiotherapy (SRT) for treating large arteriovenous malformations (AVMs). METHODS: The authors analyzed 7 pediatric AVM cases treated with volume-staged stereotactic radiosurgery (SRS) using the Gamma Knife Perfexion at the University of California, San Francisco. The target and normal tissue contours from each case were exported for hypofractionated treatment planning based on the Gamma Knife Extend system or the CyberKnife SRT. Both the Gamma Knife Extend and CyberKnife treatment plans were matched to yield the same level of target coverage (95%-98%) and conformity indices (1.24-1.46). Finally, hypofractionated treatment plans were compared with volume-staged treatment plans for sparing normal brain by using biologically equivalent 12-Gy normal brain volumes. RESULTS: Hypofractionated Gamma Knife Extend and CyberKnife treatment plans exhibited practically identical sparing of normal brain for the studied cases. However, when matching such values with volume-staged treatments for the biological effective dose, only conservative dose fractionation schemes, such as 27.3 Gy in 5 fractions and 25 Gy in 4 fractions, were found to be comparable to the volume-staged treatments. On average, this represents a mean 18.7% ± 7.3% reduction in the single-fraction biologically equivalent dose for hypofractionated treatments versus the reference volume-staged treatments (p < 0.001). CONCLUSIONS: Volume staging remains advantageous over hypofractionation in delivering a higher dose to the target and for better sparing of normal brain tissue in the treatment of large AVMs. More clinical data are needed, however, to justify the clinical superiority of this increased dose when compared with a hypofractionated treatment regimen.