The incidence of primary central nervous system lymphoma (PCNSL) has been on the rise in the setting of immunodeficiency syndromes such as acquired immune deficiency syndrome (AIDS). Its diagnosis has been facilitated by the advent of a cerebrospinal fluid (CSF) Epstein-Barr virus (EBV) PCR assay. The reported high sensitivity and specificity of this assay has made it the cornerstone of diagnosis of PCNSL, replacing more traditional methods such as an open CNS biopsy. Here, we have described a patient with a known history of C3 AIDS presenting with lower extremity weakness and eventual myelopathy who was later diagnosed as having intramedullary PCNSL after detection of EBV DNA in his CSF. After failing to respond to radiotherapy, he underwent a spinal cord biopsy revealing intramedullary tuberculoma. This case illustrates the risk of misdiagnosis with this assay and the importance of histological confirmation of a pathological lesion prior to implementation of therapy.