Background: There is an increasing incidence of patients infected with human immunodeficiency virus (HIV) in India. The neurological manifestations of the disease are being seen more frequently. The nervous system is the most frequent and serious target of HIV infection. Aims and Objectives: To elucidate the spectrum of neurological involvement in patients with HIV infection at a tertiary care teaching hospital in western Maharashtra. We investigated various neurological manifestations of HIV including opportunistic infections (OPIs) and non-opportunistic infections (non- OPIs). Settings and Design: This was a retrospective observational study conducted at a tertiary care center in western Maharashtra over a period of 2 years from Jan 2009 to Dec 2010. Materials and Methods: A total of 81 HIV seropositive patients of both genders, of age >18 years, with neurological manifestations admitted at a tertiary care center were studied for clinical parameters, laboratory investigations and imaging. Statistical Analysis: Data were coded by numbers and double entered in a computer software SSPE-11 trial version. Results: A total of 179 patients admitted with HIV infection, of which 81 (45.25%) presented with neurological manifestations (neuro-acquired immunodeficiency syndrome [AIDS]), were enrolled in the study. Overall, 53 (65.43%) patients were male (34 years ± 11) and 28 (34.56%) were female (29 years ± 8). The male patients were outnumbered compared with the female patients, with P = 0.02. A total of 45 (55.55%) patients had OPIs and 36 (44.44%) patients had non-oppurtunistic neurological manifestations affecting the nervous system (P = 1573; insignificant). A total of 15 (18.51%) patients had immune reconstitution syndrome on antiretroviral therapy (A total of 11 (13.58%) patients had seizures, eight (9.87%) had ischemic stroke, eight (9.87%) had aseptic meningitis, two (2.46%) had intracranial hemorrhage, two (2.46%) had vacuolar myelopathy, four (4.93%) had AIDS-associated dementia, three (3.70%) had Guillain Barré syndrome (GBS), two (2.46%) had acute motor sensory axonal neuropathy (AMSAN), one (1.23%) had chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and two (2.46%) had mononeuritis multiplex cranialis. A total of 17 (20.98%) patients had TB meningitis, 11 (13.58%) had cryptoccocal meningitis, one (1.23%) had Pott’s spine, two (2.46%) had progressive multifocal leukoencephalopathy (PMLE), two (2.46%) had herpes zoster, one (1.23%) had herpes simples encephalitis and one (1.23%) had cerebral toxoplasmosis. The CD4 was significantly low in patients with PMLE, ADC (AIDS Dementia Complex) and cryptoccocal meningitis compared with other neurological manifestations (P < 0.002). The case fatality rate was 7.4% (6/81). Mortality was significantly high in patients with cryptoccocal meningitis and PMLE compared with the other neurological manifestations (P = 0.034). Conclusion: We found a high prevalence of neurological manifestations in HIV seropositive patients (45.25%) in this setting. Central nervous system (CNS) tuberculosis was the most common secondary infection seen in HIV patients. Cryptococcal meningitis was the next common infection, which showed a striking male preponderance. The most common non-infectious lesions included cerebrovascular events, followed by neoplasms. Neuropathies and myelopathies were the least common neurological manifestations in patients with HIV infection. This study revealed not only the high prevalence of various neurologic events but also their nature, clinical presentation and symptoms. A neuropsychological assessment should be mandatory for all HIV-positive patients. CNS OPI indicates progression of HIV infection toward AIDS, and is useful as a reference to starting ART in settings where facilities for determination of CD4 counts are not available.