A 72-year-old man was admitted with left homonymous hemianopsia and hemiparesis. Magnetic resonance imaging revealed a heterogeneously enhanced lesion in the right parietal lobe. A brain biopsy showed acute demyelination without malignancy, which led to a diagnosis of tumefactive multiple sclerosis (MS). The patient received corticosteroid therapy and experienced clinical and radiological improvement. Six months later, new lesions appeared, and a second biopsy revealed proliferation of dysplastic lymphocytes. This led to a revised diagnosis of primary central nervous system lymphoma (PCNSL). Because PCNSL mimics MS both clinically and radiologically, PCNSL is difficult to diagnose. Performing repeated brain biopsies may therefore be required when PCNSL is strongly suspected.