OBJECTIVE Ventriculostomy is a relatively common neurosurgical procedure, often performed in the setting of acute hydrocephalus. Accurate positioning of the catheter is vital to minimize morbidity and mortality, and several anatomical landmarks are currently used. The aim of this study was to prospectively evaluate the relative performance of 3 recognized trajectories for frontal ventriculostomy using imaging-derived metrics: perpendicular to skull (PTS), contralateral medial canthus/external auditory meatus (CMC/EAM), and ipsilateral medial canthus/external auditory meatus (IMC/EAM). METHODS Participants completed 9 simulated ventriculostomy attempts (3 of each trajectory) on a model head with Medtronic StealthStation coregistered imaging. Performance measures were distance of the ventricular catheter tip to the foramen of Monro (FoM) and presence of the catheter tip in a lateral ventricle. RESULTS Thirty-one individuals of varying seniority and prior ventriculostomy experience performed a total of 279 simulated freehand frontal ventriculostomies. The PTS and CMC/EAM trajectories were found to be significantly more likely to result in both the catheter tip being closer to the FoM and in a lateral ventricle compared with the IMC/EAM trajectory. These findings were not influenced by the prior ventriculostomy experience of the participant, corroborating the significance of these results. CONCLUSIONS The PTS and CMC/EAM trajectories were superior to the IMC/EAM trajectories during freehand frontal ventriculostomy in this study, and further data from studies incorporating varying ventricular sizes and bur hole locations are required to facilitate a change in clinical practice. In addition, neuronavigation and other guidance techniques for ventriculostomy are becoming increasingly popular and may be superior to freehand techniques, necessitating further prospective data evaluating their safety, efficacy, and feasibility for routine clinical use.