Purpose: To report on the development of visually significant maculopathy associated with blood-brain barrier disruption (BBBD) therapy for the treatment of central nervous system (CNS) lymphoma. Design: Retrospective case series. Methods: Chart review of 20 patients undergoing BBBD therapy for treatment of CNS lymphoma at the Cleveland Clinic. Patients with documented maculopathy were included in analysis. Results: Seven (54%) of 13 patients were identified with new macular retinal pigment epithelium (RPE) changes after BBBD treatment. The RPE changes consisted of fine clumps of hyperpigmentation in the foveal region associated with variable degrees of RPE loss. These changes were bilateral but often asymmetric. Two patients had decreased visual acuity resulting from maculopathy. One patient had documented progression of maculopathy after completion of treatment. Conclusions: Maculopathy is a frequent finding after BBBD therapy for CNS lymphoma.