Objective: To describe and correlate neurotoxicity indicators in long-term primary CNS lymphoma (PCNSL) survivors who were treated with high-dose methotrexate-based regimens with or without whole-brain radiotherapy (WBRT).Methods: Eighty PCNSL survivors from 4 treatment groups (1 with WBRT and 3 without WBRT) who were a minimum of 2 years after diagnosis and in complete remission underwent prospective neuropsychological, quality-of-life (QOL), and brain MRI evaluation. Clinical characteristics were compared among treatments by using the x 2 test and analysis of variance. The association among neuroimaging, neuropsychological, and QOL outcomes was assessed by using the Pearson correlation coefficient. Results:The median interval from diagnosis to evaluation was 5.5 years (minimum, 2 years; maximum, 26 years). Survivors treated with WBRT had lower mean scores in attention/executive function (p 5 0.0011), motor skills (p 5 0.0023), and neuropsychological composite score (p 5 0.0051) compared with those treated without WBRT. Verbal memory was better in survivors with longer intervals from diagnosis to evaluation (p 5 0.0045). On brain imaging, mean areas of total T2 abnormalities were different among treatments (p 5 0.0006). Total T2 abnormalities after WBRT were more than twice the mean of any non-WBRT group and were associated with poorer neuropsychological and QOL outcomes.Conclusions: Our results suggest that in patients treated for PCNSL achieving complete remission and surviving at least 2 years, the addition of WBRT to methotrexate-based chemotherapy increases the risk of treatment-related neurotoxicity. Verbal memory may improve over time. Classification of evidence:This study provides Class III evidence that in patients treated for PCNSL achieving complete remission and surviving at least 2 years, the addition of WBRT to methotrexatebased chemotherapy increases the risk of treatment-related neurotoxicity. High-dose methotrexate is the most widely used drug for primary CNS lymphoma (PCNSL). In combination with whole-brain radiotherapy (WBRT), high-dose methotrexate improved survival rates over WBRT alone. However, delayed treatment-related neurotoxicity emerged as a significant disabling complication of the combined treatment.1-9 Single-drug and multidrug high-dose methotrexate-based regimens without WBRT have been used in an effort to increase survival while avoiding the risk of delayed neurotoxicity. [10][11][12][13][14][15] In patients older than 60 years treated with WBRT, virtually all long-term survivors develop this complication. In patients younger than 60 years, neurotoxicity rates ranging from 26% to 63% have been reported. 2,6 However, the true risk ofFrom the Oregon Health