Background— Focal brain lesions associated with HIV infection can be due to cerebrovascular diseases, primary CNS lymphoma, toxoplasmosis, progressive multifocal leukoencephalopathy or other opportunistic infections. We report a challenging case of an adult HIV infected male with focal brain lesions. Case Description-- A 62 years old male, presented with history of cough with mucoid expectoration for 3 months and abnormal behaviour for 2 weeks. Clinical examination revealed delayed obeying of commands and no other sensorimotor deficits. MRI brain revealed ill-defined space occupying lesions involving bilateral frontal lobes. HIV antibodies and HBsAg tests were positive. CT chest revealed multiple cavitatory lesions in left upper lobe. Pharyngeal candidiasis was seen during bronchoscopy. Bronchoscopic alveolar lavage revealed Nocardia species. Tests for MTB were negative. Lung biopsy showed Cytomegalovirus pneumonitis with Aspergillosis. PET scan revealed non FDG avid gliotic changes in brain. CSF and bone-marrow examinations were normal. Brain lesion was considered to be a manifestation of Nocardiosis and biopsy was planned. CD4 count was 103/mm3. Intravenous ceftriaxone, ganciclovir, caspofungin, fluconazole and oral septran were started. Patient was started on HAART(Tenofovir, lamivudine, efavirenz) 1 week later, after explaining the risk of Immune reconstitution inflammatory syndrome. CNS lesion biopsy revealed High grade B-cell Non- Hodgkin’s lymphoma. Palliative external Radiotherapy to whole brain was given. The patient has improved clinically and is on regular follow up from 1 year. Conclusion— Extensive evaluation and work up is required in cases of focal brain lesions in patients with HIV. Brain biopsy often provides the definitive diagnosis.