PURPOSE: The neurocognitive decline is one of the main limiting factor of whole brain irradiation. This study evaluate the correlation between the site of (Primary Central Nervous System Lymphoma) PCNSL lesions and the hippocampal region in order to explore the feasibility of routinely sparing of the hippocampus during whole-brain radiotherapy (WBRT) to prevent radiation-induced neurocognitive decline. METHODS AND MATERIALS: Patients (>18 years, ECOG <4) with pathologically proven PCNSL and MRI image pre-treatment were retrospectively reviewed. All patients had received high-dose of methotrexate (HD-MTX) before WBRT. T1-weighted, post-contrast axial MR image sets obtained prior to cranial irradiation were imported on Varian Eclipse treatment planning system, version 11 (Varian Medical Systems) and registered with the simulation CT. The hippocampus as well as each PCNSL lesions were contoured. Three dimensional envelopes surrounding the hippocampus were generated adding 5, 10, and 15 mm and the distance of brain lesions were recorded as <5 mm, 5 to <10 mm, 10 to <15 mm, and >15 mm from the hippocampus. The minimum margin of 5 mm was taken account for systematic setup error and dose fall-off between whole brain clinical target volume and the hippocampus. RESULTS: Between 2006 and 2013, 23 patients were treated and 17 pts with 35 lesions were eligible for this study. In this sample PCNSL lesions were positioned: parietal lobe (28,6%), deep brain structures (20%), frontal lobe (17,1%), temporal lobe (14,3%), brainstem (8,6%), other sites (11,4%). Six patients were affected by multiple lesions. In 7/17 patients (41.2%) PCNSL lesion was distant from the hippocampus region less than 5 mm. Eight out 35 lesion (22.8%) were localized within 5 mm of hippocampal region, three of them involved the hippocampus. Over 15 mm of the hippocampus we observed 51,4% (n = 18) of brain lesions, while 11,4% (n = 4) and 14.4% (n = 5) were between 10-15 mm. CONCLUSIONS: These data show that routinely sparing of the hippocampus region is not recommended; it must be considered when the spatial distribution of PCNSL is more than 5 mm.