HIV-associated primary central nervous system lymphoma (PCNSL) is an aggressive malignancy that usually occurs in the setting of advanced immunosuppression. Its atypical radiological behavior poses a challenge to the differential diagnosis with opportunistic infections of the CNS. Here we present a case of PCNSL in the setting of AIDS: after a comprehensive work-up of radiological and laboratory assessments, brain biopsy was necessary to uncover the diagnosis.