Primary cerebral lymphoma in immunocompromised patients is rare and challenging to diagnose. Its presentation can have similarities with other opportunistic diseases like cerebral toxoplasmosis and tuberculoma, to name a few, which may affect the subsequent management. Here, we report a case of a gentleman with human immunodeficiency virus (HIV) who presented with clinical features of fever, confusion, and generalized lethargy. His imaging features mimicked those of central nervous system (CNS) tuberculosis (TB), and he was treated for one. Unfortunately, the patient failed to respond to the anti-tuberculosis treatment and continued to deteriorate eventually succumbing to his illness. Brain histopathology biopsy confirmed the diagnosis of diffuse large B-cell lymphoma. We aim to illustrate the importance of a high index of suspicion with timely action taken whenever the anticipated finding or response to treatment is not observed. Multiple imaging modalities coupled with biochemistry and histopathological investigations should be considered in discriminating competing diagnoses.