Background: There are several cost issues separating the use of surgical navigation systems and stereotactic frames for simple biopsy which may have implications in this era of health care cost control. Objective: To evaluate the diagnostic, therapeutic role, efficacy, safety, complications and cost of stereotactic brain biopsy performed with a frameless versus a frame-based method. Patients and Methods: This was a prospective study including 20 patients with deep seated brain lesion, morphological stereotactic surgeries performed with frame based stereotaxy (Group A) and frameless stereotaxy (Group B) as main management modality of their treatment, over two years from January 2019 to January 2021. All patients were examined and checked at Al-Azhar University Hospitals, Egypt. Data were collected regarding patient demographics, type of anesthesia, diagnostic yield, total operating room time, length of hospitalization and complication of the two procedures performed. Results: There were no significant differences between the frame-based and frameless biopsy groups with regard to patient demographics, overall histopathology, proportion of nondiagnostic biopsies, incidence of complications. All the cases underwent frame-based stereotactic procedures done under local anesthesia, while the cases underwent frameless stereotactic procedures done under general anesthesia in 9 cases (90%), and local anesthesia in one case (10%). The total operating room time in frame-based biopsies ranged from 90 to 130 min (Mean 106.00, SD =14.30), while in frameless biopsies ranged from 120 to 195 min (Mean 167.00, SD = 22.75). The total time of hospitalization in frame-based stereotactic brain biopsy ranged from 1 to 3 days,  mean 1.90+ SD = 0.56), while the total time of hospitalization in frameless stereotactic brain biopsy ranged from 3 to 8 days (Mean 5.1+ SD = 1.37). Conclusion: Frame-based and frameless stereotactic biopsy approaches were equally effective at providing a tissue diagnosis with minimum morbidity and mortality. The frame-based approach, however, required significantly less anesthesia resources, less operating room time and shorter hospital stays, and thus should still be considered a first line approach for stereotactic brain biopsy.