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Purpose: To investigate outcomes in vitreoretinal lymphoma (VRL) presenting with or without sub-retinal pigment epithelial (sub-RPE) infiltration., Design: Retrospective, comparative analysis., Subjects: Patients with VRL at a single center from January 1, 1984, through July 30, 2018., Methods: Record review was conducted for clinical features, treatments, and outcomes of tumor control, visual acuity (VA), and death., Main Outcome Measures: Ocular tumor control and VA outcome., Results: The study involved 168 eyes of 95 patients with VRL, of which 45 (27%) eyes of 32 patients had sub-RPE infiltration. Comparison (of patients with vs. without sub-RPE infiltration) showed similar presenting features of mean patient age (65 vs. 68 years, P = 0.30), percentage of males (53% vs. 56%, P = 0.83), white race (84% vs. 87%, P = 0.77), bilateral ocular involvement (78% vs. 75%, P = 0.80), and VA of 20/40 or better (40% vs. 50%, P = 0.30), 20/50 to 20/200 (42% vs. 31%, P = 0.20), or worse than 20/200 (18% vs. 19%, P = 0.99). Lymphoma subtype was diffuse large B cell (59% vs. 52%) or unspecified (41% vs. 44%, P = 0.85). Follow-up data were available for 125 eyes of 70 patients. Overall treatment included systemic chemotherapy (53% vs. 64%, P = 0.29), intravitreal chemotherapy (59% vs. 28%, P = 0.005), and external beam radiotherapy (59% vs. 94%, P < 0.001). Initial ocular tumor control occurred (91% vs. 94%, P = 0.68) with subsequent recurrence (35% vs. 17%, P = 0.07). Outcomes at final follow-up (mean 24 vs. 25 months, P = 0.82) revealed ocular tumor complete regression (68% vs. 86%, P = 0.03), partial regression (3% vs. 7%, P = 0.44), or active persistent or recurrent disease (29% vs. 7%, P = 0.002). Final VA was 20/40 or better (39% vs. 53%, P = 0.18), 20/50 to 20/200 (26% vs. 34%, P = 0.53), or worse than 20/200 (34% vs. 13%, P = 0.007). Vitreoretinal lymphoma was associated with central nervous system lymphoma (41% vs. 59%, P = 0.13) or systemic lymphoma (16% vs. 21%, P = 0.60). Death occurred (63% vs. 54%, P = 0.51) at mean age (69 vs. 69 years, P = 0.94)., Conclusion: Sub-RPE infiltration in VRL is associated with more persistent or recurrent ocular tumor and poorer VA outcome, but no difference in frequency of central nervous system/systemic lymphoma or death. Further studies are required to determine whether earlier, more aggressive, or prolonged ocular therapy for patients with VRL presenting with sub-RPE infiltration could improve these factors., (Copyright © 2019 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)