Abstract Whole brain radiation therapy (WBRT) to primary central nervous system lymphoma (PCNSL) correlate with brain atrophy and leukoencephalopathy on serial computed tomography or MRI scans, negatively impacting cognitive function and quality of life. We retrospectively evaluated 53 patients with histologically proven PCNSL who underwent cerebrospinal fluid (CSF) examination including β2-MG, sIL2R, CXCL13, and IL-10 preoperatively. All patients were newly diagnosed and followed up every 3 months from the day they were discharged from the hospital. Follow up period is at least 1 year from last day of chemotherapy. Clinical data included patient demographics, radiological and characteristics; whole brain volume (mm2) calculated from BainLabTM automatically, Global Cortical Atrophy (GCA) for global brain atrophy, Medial Temporal Atrophy (MTA) for temporal atrophy, and Fazekas scale for white matter lesions. The unpaired t test and multivariable liner regression were used to examine the clinical, CSF and radiological characteristics of patients. The mean age at symptom onset was 65.2 years (47-85 years). Thirty three of 53 (62%) patients underwent WBRT with chemotherapy (WBRT group). In all patients, multivariable analysis revealed WBRT correlate with brain volume reduction (p=0.0005) and progression of temporal lobe atrophy (p=0.0056). In addition, Age correlated with increasing white matter lesions at 1 year after chemotherapy (p=0.0422). In WBRT group, multivariable analysis indicated that high CSF IL-10 level accelerated brain volume reduction (p=0.0122) and temporal lobe atrophy (p=0.0343) at 6 months after chemotherapy. However, there were no significant factor for influencing brain atrophy at 1 year. Higher IL-10 ( > 100mg/ml) level demonstrated higher brain atrophy rate (p=0.0366) and severe temporal atrophy at 1 year (p=0.0214). In elderly patients with high preoperative CSF IL-10 levels, cerebral atrophy and toxic leukoencephalopathy may progress in short period of time after WBRT. We should consider treatment strategy that avoid WBRT, such as R-MPV chemotherapy, for PCNSL patients.