Background: Prognosis and response assessment are crucial to guide PCNSL patient therapeutic management. β2MG is a well-known prognostic factor of systemic lymphoma but its prognostic value in PCNSL remains uncertain. Objective is to evaluate the prognostic value of β2MG in CSF in PCNSL patients. Methods: We prospectively analyzed the CSF β2MG concentration in all newly PCNSL patients referred to our institution between March 2014 and November 2021 for whom lumbar punction was allowed. β2MG analysis was performed at diagnosis before the first treatment administration, after 2 and 4 treatment cycles. The clinical, radiological, histological, biological and treatment data were retrospectively collected. Results: Thirty-six patients were included with a median age of 71.8 (range 42.5 – 85.3). All patients presented with DLBCL CD20+ lymphoma. Median KPS was 70 (range, 30 – 100). Median dose of prednisone at diagnosis was 60 mg (range, 0 – 1000). Thirty-two patients (88.9%) received polychemotherapy with high-dose methotrexate as first line treatment. In CSF, median β2MG was 3.55 mg/L (range, 0.88 – 19.24), median IL10 was 35.0 pg/mL (range, 3.0 – 2843) and median IL6 was 22.1 pg/mL (range, 2.0 – 120). Only 14% and 16% of patients presented with normal CSF and blood β2MG rate at diagnosis, respectively. Five patients presented with meningitis involvement. CSF β2MG was independent from blood β2MG (p = 0.861), from CSF IL10 (p = 0.379), from CSF IL6 (p = 0.479) and from blood LDH (p = 0.685). Complete, partial responses or progressive disease were observed in 18 (54.5%), 10 (30.3%) and 5 (15.2%) patients respectively. CSF β2MG concentration tended to be correlated to patient response (p = 0.129). The rates of complete response were 65% and 44% for low (< median) and high (> median) CSF β2MG rates, respectively. At last follow-up, 17 patients (47%) had relapsed, and 11 patients (31%) died. Median progression-free survival (PFS) and overall survival (OS) were 21.2 months (95%CI: 5.9 – 36.4) and 47.6 months (95%CI not estimable due to the low number of events), respectively. In univariate analysis, low KPS and high CSF β2MG were associated with poor PFS (p = 0.002 and p = 0.008, respectively) with no detectable impact of blood β2MG. CSF IL10 and IL6 were not associated with patient outcome. In multivariate analysis high CSF β2MG tended to remain associated with worse PFS (p = 0.087, HR: 2.784, 95%CI: 0.862 – 8.987). In responder patients, CSF β2MG was significantly decreased at 4 months after first line treatment initiation (p = 0.005). Conclusions: CSF β2MG may exhibit a prognostic value in PCNSL patients. These results need to be validated in a larger prospective study.