Temozolomide is an oral alkylating agent with moderate side effects compared to other agents. However, the development of secondary malignancies following temozolomide has been reported. We describe the first case of primary central nervous system lymphoma (PCNSL) occurrence following glioblastoma treatment. A 69-year-old male was admitted to our hospital with a chief complaint of headache and dysnomia for six months. A ring-enhanced mass of the left temporal lobe was observed and gross total removal was performed. The tumor was pathologically diagnosed as isocitrate dehydrogenase (IDH)-wildtype glioblastoma and he received 60 Gy of local irradiation in 30 fractions, with concurrent temozolomide at a dose of 75 mg/m2. Grade 2 lymphopenia was discovered during treatment. Within 6 months, the patient developed a right parietal intra-axial tumor without local recurrence and was given 150-200 mg/m2 oral temozolomide for five consecutive days of a 28-day cycle. Within five cycles of temozolomide, complete remission was observed; however, after the eighth cycle, a new lesion in the right temporal lobe was discovered. Surgical removal was performed and histological findings were consistent with diffuse large B-cell lymphoma, and the final diagnosis of Epstein-Barr virus negative PCNSL was established.