Introduction In the modern era of frameless stereotaxis (FL), the role of frame-based (FB) stereotactic needle biopsy is evolving. Methods Retrospective review of prospective database of 106 lesions in 91 consecutive patients undergoing FB stereotactic needle biopsy with a systematic “geologic core” technique by a single surgeon. Diagnostic accuracy was calculated comparing biopsy diagnosis with final pathology in 11 patients who underwent subsequent surgical resection. All instances of intra-operative bleeding through the needle were prospectively noted and compared with post-biopsy CT scan. Lesions were classified as risky for FL technique if they were (1) infratentorial or pineal, (2) within 10 mm of the circle of Willis or root of the Sylvian fissure, or (3) within 10 mm of deep cerebral veins. Results Diagnostic yield was 94%. Diagnostic accuracy was 91%. Of 18 lesions involving the corpus callosum, 13 (72.2%) were GBM 2 were anaplastic astrocytoma, and 1 each were found to be anaplastic oligodendroglioma, primary central nervous system lymphoma (PCNSL) and tumescent MS. Of 25 multifocal lesions, malignant primary brain tumor was diagnosed in 17 (68%) (11 GBM, 3 PCNSL, 2 anaplastic ologodendroglioma, and 1 anaplastic astrocytoma). Mortality was 0%. Three patients developed temporary neurologic deficits and one had permanent deficit. Absence of persistent blood through the biopsy needle had a negative predicative value of 98.8% for subsequent neuroimaging blood >5 mm diameter. According to our criteria, 80% of patients would have been candidates for FL biopsy. Conclusions Stereotactic biopsy is an effective, safe and important technique for histologic diagnosis of brain lesions, particularly for multifocal and corpus callosum lesions. Post-biopsy CT can be safely reserved for patients who demonstrate persistent bleeding through the biopsy needle. FB stereotaxy remains an important technique for the 20% with small or deep seated lesions or when it is advantageous to avoid an incision, a burr hole or general anesthesia.