Recent studies have implicated long-term pentosan polysulfate use with vision loss from a newly described macular condition. Affected patients report difficulty with reading and adjusting to dim lighting, and they occasionally develop severe visual disability. Macular changes resemble those seen in age-related macular degeneration, potentially leading to misdiagnosis. The objectives of this Current Commentary are to summarize studies evaluating the association between pentosan polysulfate use and macular disease, to educate pentosan polysulfate prescribers about the clinical manifestations of this condition, and to provide recommendations for screening at-risk patients.