A comparison study is presented, which examines the outcome, complications and cost of stereotactic brain biopsy performed with a frameless versus a frame-based method. The technique of frameless stereotactic biopsy has been shown previously, in both laboratory and in vivo studies, to achieve a level of accuracy at least equal to frame-based biopsy. The investigators have validated the technique in a large clinical series. The frameless and frame-based series were concurrent, comprising 76 and 79 cases, respectively. The frameless stereotactic technique involved standard needle biopsy, targeted by an image-guidance system and directed by a novel rigid adjustable instrument-holder. Frame-based biopsies were performed with the CRW and Leksell systems. There were no significant differences in the demographics, lesion site, size and pathologies between the groups. Operating theatre occupancy and anaesthetic time were both significantly shorter for the frameless series than the frame-based series (p < 0.0001). In addition, the complication rate in the frameless biopsy series was significantly lower than in the frame-based series (p = 0.018). This resulted in lower ITU bed occupancy (p = 0.02), shorter mean hospital stay (p = 0.0013) and significant cost savings (p = 0.0022) for the frameless stereotactic biopsy group, despite the greater use of more expensive MRI in these cases. This comparison study demonstrates that the superior imaging, target visualization and flexibility of the technique of frameless stereotactic biopsy translates into tangible advantages for safety, time and cost when compared with the current gold-standard of frame-based biopsy. The principles are discussed and the authors propose a definition for the term 'frameless stereotaxy'.