OBJECTIVEThe purpose of this study was to compare the accuracy of Neurolocate frameless registration system and frame-based registration for robotic stereoelectroencephalography (SEEG).METHODSThe authors performed a 40-trajectory phantom laboratory study and a 127-trajectory retrospective analysis of a surgical series. The laboratory study was aimed at testing the noninferiority of the Neurolocate system. The analysis of the surgical series compared Neurolocate-based SEEG implantations with a frame-based historical control group.RESULTSThe mean localization errors (LE) ± standard deviations (SD) for Neurolocate-based and frame-based trajectories were 0.67 ± 0.29 mm and 0.76 ± 0.34 mm, respectively, in the phantom study (p = 0.35). The median entry point LE was 0.59 mm (interquartile range [IQR] 0.25–0.88 mm) for Neurolocate-registration–based trajectories and 0.78 mm (IQR 0.49–1.08 mm) for frame-registration–based trajectories (p = 0.00002) in the clinical study. The median target point LE was 1.49 mm (IQR 1.06–2.4 mm) for Neurolocate-registration–based trajectories and 1.77 mm (IQR 1.25–2.5 mm) for frame-registration–based trajectories in the clinical study. All the surgical procedures were successful and uneventful.CONCLUSIONSThe results of the phantom study demonstrate the noninferiority of Neurolocate frameless registration. The results of the retrospective surgical series analysis suggest that Neurolocate-based procedures can be more accurate than the frame-based ones. The safety profile of Neurolocate-based registration should be similar to that of frame-based registration. The Neurolocate system is comfortable, noninvasive, easy to use, and potentially faster than other registration devices.