We report the case of a 24-year-old woman who received immunosuppressive treatment for systemic lupus erythematosus. In her past medical history, she had been treated for disseminated toxoplasmosis (ocular and cardiac). Four months later, she was hospitalized and treated for a presentation suggestive of cerebral toxoplasmosis. The diagnosis of primary central nervous system lymphoma (PCNSL) was finally made using stereotactic brain biopsy; however, the evolution was rapidly fatal within 6 days after admission. We discuss the challenge of differential diagnosis between cerebral toxoplasmosis and PCNSL in immunocompromised patients and the role of brain biopsy in patient management.