Primary central nervous system lymphoma is notoriously challenging to diagnose in immunocompetent patients as it is an uncommon diagnosis. We present a case of synchronous diagnosis with tuberculosis. A 60-year-old woman presented with cognitive difficulties, memory loss, social withdrawal, unintentional weight loss, and night sweats, the work-up of which ultimately identified multiple brain lesions and mediastinal adenopathy. Brain biopsy showed lymphohistiocytic infiltrate, while mediastinal node histopathology showed necrotizing granulomas, and cultures grew Mycobacterium tuberculosis. The patient was initiated on anti-tuberculosis therapy. However, follow-up brain MRI demonstrated disease progression, prompting repeat brain biopsy, which in turn confirmed the diagnosis of diffuse large B-cell lymphoma. Although unrelated synchronous diagnoses are rare, the potential for clinically significant confounding is considerable-particularly where disease markers may overlap, as is often the case with infectious, inflammatory, and neoplastic processes. The present case illustrates the importance of diligence in ruling out competing diagnosis, and timely action when an anticipated finding or response-to-treatment is not observed.