We describe the case of a man who developed a dementing illness with leukoencephalopathy while receiving low dose weekly oral methotrexate (MTX) therapy for rheumatoid arthritis. The white matter changes seen on magnetic resonance imaging and computerized tomogram scan were the same as those seen in cases of leukoencephalopathy that have been reported in patients receiving intravenous or intrathecal methotrexate. Extensive investigation excluded other known causes of white matter disease. Although no improvement either subjectively or objectively occurred in his mental status after cessation of treatment with MTX, he has remained stable. We believe that this may represent a case of oral MTX induced leukoencephalopathy, which has not previously been reported.