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A 57-year-old man was admitted to our hospital because of persistent blurred vision for 5 months. He had opacity in the vitreous body and white lesions in the retina of the right eye. Although cytological examinations of the vitreous samples revealed Class II, the diagnosis of primary intraocular lymphoma (PIOL) was made by detecting both IgH rearrangement by PCR and an elevated ratio of IL-10/IL-6 concentration in the vitreous sample. Systemic examinations were performed simultaneously and no extra-ocular involvement was detected. Intravitreal methotrexate (MTX) injections were effective and the lesions disappeared following injections. Two months later (10 months after appearance of the right eye lesion), however, the same lesions appeared in the left eye. Cytological examinations of the left vitreous sample revealed Class V by detecting large abnormal lymphocytes. Although intravitreal MTX injections were also effective, central nervous system (CNS) involvement appeared only 2 months after the left eye lesions appeared. Open biopsy was performed and a diagnosis of diffuse large B-cell lymphoma was made. Despite starting with high-dose MTX, he died of CNS disease 1 year and 8 months after onset. Diagnosis of PIOL is difficult. Since local treatment was considered insufficient, an optimal treatment strategy for PIOL should be established.