<p>Stereotactic brain biopsy is a standard neurosurgical procedure for diagnosing intracranial lesions. Lesion size is often considered a limiting factor; however, the safety and diagnostic yield of biopsies in lesions &lt; 10 mm remain poorly defined. This study evaluated the outcomes of frame-based stereotactic biopsies for lesions &lt; 10 mm in size compared with larger lesions. We retrospectively analyzed all consecutive adult patients who underwent frame-based stereotactic biopsy for targeted lesions &lt; 10 mm in maximum diameter between April 2009 and April 2024 at our institution. Each case was matched (1:3) with patients with lesions ≥ 10 mm based on age, lesion location, and contrast enhancement. The primary endpoint was diagnostic yield, and the secondary endpoints included complications graded using a validated severity scale. Continuous variables were compared using Student’s t-test or Wilcoxon’s rank-sum test. Of the 2,347 patients who underwent frame-based stereotactic biopsy during the inclusion period, 74 patients (3.2%) with lesions &lt; 10 mm were compared with 222 controls. Among the 296 patients, the overall diagnostic yield was 95%. The diagnostic yields did not significantly differ between the small and large lesion groups (91.9% vs. 96.0%, p = 0.2). Non-tumoral pathology was the main factor associated with non-diagnostic results. Symptomatic complications occurred in 4.1% of patients, with no significant difference between the groups (1.4% vs. 4.9%; p = 0.3). No severe complications occurred in the &lt; 10 mm group. The overall mortality rate was 1.3%, with no mortality in the small-lesion cohort. Frame-based stereotactic biopsy of lesions &lt; 10 mm is safe and effective, with a diagnostic yield comparable to that of larger lesions and no excess risk of complications. These findings challenge long-standing assumptions discouraging the biopsy of small lesions and support its use when clinically indicated.</p>