OBJECTIVE: To systematically review biopsies of Childhood primary small vessel CNS vasculitis (SVcPACNS) patients and inflammatory and epilepsy controls and to determine characteristic features defining the diagnosis of SVcPACNS. BACKGROUND: SVcPACNS is an increasingly recognized inflammatory brain disease with high morbidity and mortality mandating an elective brain biopsy to confirm the diagnosis. DESIGN/METHODS: A previously developed, standardized brain biopsy review instrument was applied to consecutive full thickness brain biopsies of pediatric cases and controls collected at a single center. Standardized stains including Hematoxyllin & Eosin, histochemistry of immune cell subsets plus electron microscopy. Nine North American expert neuropathologists were blinded reviewed to the patient’s presentation, diagnosis and therapy. All biopsies were de-identified and scored independently by two reviewers. Univariate analyses compared variable between groups; correspondence analysis determined the multi-dimensional relationship of histological variables and patient diagnoses. RESULTS: A total of 31 brain biopsy specimens of children with SVcPACNS, 12 with epilepsy and 11 with non-vasculitic inflammatory brain disease controls were included. Correspondence analyses revealed distinct clusters of the three diagnoses based on dimensions of location of infiltrate and subtype/ severity of inflammation. Significant histological characteristics found to set apart SVcPACNS from controls included angiocentric (p<0.01) and/or perivascular infiltrates (p=0.04), evidence of endothelial cell activation (p<0.01) and inflammation in both grey and white matter (p<0.01). The infiltrate was found to be primarily T-cell mediated (CD3+ 86[percnt], CD8+ 90[percnt]) only 27[percnt] of SVcPACNS biopsies had evidence of B cells. Features reported in adult PACNS including granulomas, necrosis or fibrin deposits were absent in all biopsies. Leptomeningeal inflammation was non-diagnostic. CONCLUSIONS: Distinct histological features were identified on brain biopsies of SVcPACNS and may help define the disease. These were absent in biopsies of children with epilepsy and non-vasculitic inflammatory brain diseases and allow for the development of diagnostic criteria.