OBJECTIVE: To compare the diagnostic yield and safety profiles of intraoperative magnetic resonance imaging (MRI)-guided needle brain biopsy with 2 traditional brain biopsy methods: frame-based and frameless stereotactic brain biopsy. METHODS: A retrospective analysis was performed of 288 consecutive needle brain biopsies in 277 patients undergoing stereotactic brain biopsy with any of the 3 biopsy methods at Brigham and Women's Hospital from 2000-2008. Variables including age, sex, history of radiation and previous surgery, pathology results, complications, and postoperative length of hospital stay were analyzed. RESULTS: Over the course of 8 years, 288 brain biopsies were performed. Of these, 253 (87.8%) biopsies yielded positive diagnostic tissue. Young age (<40 years old) and history of brain radiation or surgery were significant negative predictors for a positive biopsy diagnostic yield. Excluding patients with prior radiation or surgeries, no significant difference in diagnostic yield was detected among the 3 groups, with frame-based biopsies yielding 96.9%, frameless biopsies yielding 91.8%, and intraoperative MRI-guided needle biopsies yielding 89.9% positive diagnostic yield. Serious adverse events occurred 19 biopsies (6.6%). Intraoperative MRI-guided brain biopsies were associated with less serious adverse events and the shortest postoperative hospital stay. CONCLUSIONS: Frame-based, frameless stereotactic, and intraoperative MRI-guided brain needle biopsy techniques have comparable diagnostic yield for patients with no prior treatments (either radiation or surgery). Intraoperative MRI-guided brain biopsy is associated with fewer serious adverse events and shorter hospital stay.