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Primary brain lymphoma is a rare variant of extranodal non-Hodgkin’s B-cell lymphoma. In >90% of cases, this is diffuse large B-cell lymphoma with CD20 expression and is confined to the brain, meninges, spinal cord, and eyes. It accounts for fewer than 7% of primary brain tumors. Its incidence has been rising in recent years in immunocompetent patients in their fifth and sixth decades. The rate of relapse after initial therapy based on high-dose methotrexate and/or total brain irradiation is high. There is no consensus for treating relapse, which ranges from retreatment with high doses of methotrexate, polychemotherapy, high doses of chemotherapy backed up by autologous stem-cell transplant to intrathecal chemotherapy, with widely differing results. Given the lack of consensus and poor results, new therapy options have appeared, including immunotherapy with rituximab. At a systemic level, alongside chemotherapy, its results are very modest and limited due to the low concentration it reaches in cerebrospinal fluid (CSF). However, its intrathecal and intraventricular use, though only isolated cases have been reported, has provided promising results.