A 31-year-old man presented with seizures and cerebellar symptoms on a background of weight loss and lethargy. He was found to be infected with human immunodeficiency virus (HIV) and following radiological imaging, was commenced on treatment for presumed cerebral toxoplasmosis. Due to a lack of response, both clinically and on interval imaging, a positron-emission tomography-computed tomography and brain biopsy were undertaken, which demonstrated high-grade primary central nervous system lymphoma (PCNSL). Awareness amongst both clinicians and radiologists of the multifarious patterns of intra-cranial involvement in patients with HIV is, therefore, of utmost importance, as the treatment and prognosis of these entities are entirely different.