This study aimed to investigate the pathogenesis of a sub-acute progressive asymmetric pancerebellar syndrome in a 54-year-old man with associated mood disturbance, mild cognitive impairment and weight loss. Examination revealed a cachectic man with a reactive, teary and dysthymic affect and mild cognitive impairment. Neurological assessment revealed an asymmetric pancerebellar syndrome with no long-tract signs. An MRI of the brain showed T2-weighted hyperintensity with subtle patchy enhancement in the transverse fibres of the pons, the superior and middle cerebellar peduncles with involvement of the cerebellar white matter. Other investigations including autoimmune, vasculitic and infectious serological screening, and antineuronal antibodies were normal. Paraneoplastic screening was negative. Cererbrospinal fluid (CSF) analysis showed and elevated protein 1.14g/l, glucose 2.2 and leucocytes <1×10 6 with gram staining and multiple polymerase chain reaction (PCR) negative, including for John Cunningham (JC) papovavirus. Human immunodeficiency virus (HIV)-1 serology was positive, associated with a plasma viral load of 3802copies/ml plasma and a CD4 T cell count of 380cells/mcL (20%). Combination antiretroviral therapy was commenced. Three weeks later the patient had worsening of his symptomatology and cerebellar signs with a repeat MRI of the brain showing marked progression of the previously demonstrated T2-weighted hyperintensity involving the pons and middle cerebellar peduncles, suggesting an immune reconstitution inflammatory syndrome (IRIS). JC virus PCR in CSF was repeatedly negative as were JC virus-specific T cell responses measured in an interferon gamma ELISPOT assay. However strong responses against immunodominant HIV-specific responses were demonstrated. Our findings may suggest a novel role for restoration of HIV-specific cytotoxic T cell responses in the pathogenesis of some patients with central nervous system IRIS.