Background: Treatment for primary central nervous lymphoma (PCNSL) with chemotherapy and radiotherapy has resulted in improved survival, but some patients develop neurologic deterioration that represents a treatment-related toxic effect. This delayed neurotoxicity has been poorly defined in the literature, and the underlying mechanisms are unknown. Objective: To describe the clinical findings, time course, and pathophysiologic mechanisms associated with neurotoxicity in an attempt to generate hypotheses for future studies that address prevention and treatment of this complication of successful PCNSL therapy. Design: Retrospective review. Setting: Department of Neurology, Memorial Sloan-Kettering Cancer Center. Patients: One hundred eighty-five patients treated for PCNSL, including 43 who developed neurotoxicity. Main Outcome Measures: Potential risk factors, clinical course, and neuropsychological, neuroimaging, and histologic findings. Results: The 5-year cumulative incidence of neurotoxicity was 24%; this incidence increases over time. Neurotoxicity presented as a rapidly progressive subcortica l dementia characterized by psychomotor slowing, executive and memory dysfunctio n, behavioral changes, gait ataxia, and incontinence. Imaging findings revealed diffuse white matter disease and cortical-subcortical atrophy. Available autops y data showed white matter damage with gliosis, thickening of small vessels, and demyelination. Statistical analyses were performed, accounting for death as a c ompeting risk. Older age (P=.01), mental status changes at diagnosis (P=.04), fe male sex (P=.05), and radiotherapy (P < .001) predicted neurotoxicity on univari ate analysis, but only radiotherapy remained significant in the multivariate set ting. Conclusion: These findings suggest that the core pathophysiologic mechanis m is the interruption of frontal-subcortical circuits mediated by radiation dam age, possibly caused by progressive microvascular alterations, loss of oligodend rocyte progenitors, or oxidative stress. Background: Treatment for primary central nervous lymphoma (PCNSL) with chemotherapy and radiotherapy has resulted in improved survival, but some patients develop neurologic deterioration that said a treatment-related toxic effect. This delayed neurotoxicity has been poorly defined in the literature, and the underlying Objective: To describe the clinical findings, time course, and pathophysiologic mechanisms associated with neurotoxicity in an attempt to generate hypotheses for future studies that address prevention and treatment of this complication of successful PCNSL therapy. Design: Retrospective review. Setting: Department of Neurology, Memorial Sloan-Kettering Cancer Center. Patients: One hundred eighty-five patients treated for PCNSL, including 43 who developed neurotoxicity. Main Outcome Measures: Potential risk factors, clinical course, and neuropsychological, neuroimaging, and histologic findings. : The 5-year cumulative incidence of neuro toxicity was presented 24%; this incidence increases over time. Neurotoxicity presented as a rapidly progressive subcortica l dementia characterized by psychomotor slowing, executive and memory dysfunctio n, behavioral changes, gait ataxia, and incontinence. Imaging findings revealed diffuse white matter disease and cortical- Available autops y data showed white matter damage with gliosis, thickening of small vessels, and demyelination. Statistical analyzes were performed, accounting for death as ac ompeting risk. Older age (P = .01), mental status changes at diagnosis ( P = .04), fe male sex (P = .05), and radiotherapy (P <.001) predicted neurotoxicity on univariate ate analysis, but only radiotherapy remained significant in the multivariate set ting. Conclusion: These findings suggest that the core pathophysiologic mechanis m is the interruption of frontal-subcortical circuits mediated by radiation dam age, possibly caused by progressive microvascular alterations, loss of oligodendisrocyte progenitors, or oxidative stress.