Purpose <p>Stereotactic brain biopsies (SBB) are essential procedures to achieve histological diagnoses in brain tumor patients. Hematoma occurrence is a rare event but can lead to significant morbidity and mortality. This study investigates whether patient positioning during the procedure—semi-sitting versus supine—can affect the rate of bleeding.</p> Methods <p>We retrospectively reviewed 78 procedures of SBB, performed at Fondazione IRCCS Istituto Neurologico “C. Besta” in Milan, Italy, during the last year. The patients were allocated into two groups based on their positioning during the operation: semi-sitting (39 patients) and supine (39 patients). Medical records, operative notes, CT scans, and histological findings were reviewed. Group comparisons were performed with the Mann–Whitney test for continuous variables and with a Chi-squared test or Fisher test for categorical variables. The Benjamini–Hochberg procedure was used for multiple testing correction.</p> Results <p>The incidence of hemorrhagic complications was significantly lower in the semi-sitting group (7.7%) compared to the supine group (33.3%). Statistical analysis highlighted the semi-sitting position as a potential protective factor against bleeding (p = 0.0101).</p> Conclusion <p>The semi-sitting position during SBB seems to reduce the risk of hemorrhagic complications compared to the supine position. These findings highlight the importance of patient positioning in ensuring the safety and influencing the outcomes of neurosurgical procedures.</p>