Rituximab is a chimeric monoclonal anti-CD20 antibody that causes B-cell depletion in the peripheral B-cell pool and is used widely in several auto-immune diseases and B-cell malignancies. Patients with immuno- globulin deficiency are particularly at risk of contracting EV encephalitis and could have a lethal course.A 54-year-old lady with rheumatoid arthritis treated with four monthly Rituximab injections for the last three years was admitted with gradual onset of confusion, reduced mobility, and gastroenteritis. On admission, neurological examination showed disorientation with no focal neurological deficit. She had progressive neurological deterioration with delirium, agitation, and aphasia. MR Brain with contrast showed – hyper intense signals in pons possibility of infective rhombencephalitis.CSF examination showed – protein levels (0.52 g/dL), normal glucose, and positive Enterovirus RT-PCR. Immunoglobulin panel showed, severe hypogammaglobulinemia (Serum IgG- 3.12 g/dL (6-16) and Serum CD 19+ levels were – 0% (6-19% of lymphocyte) Subsequently, she developed decreased level of consciousness necessitating ITU admission, and received IV Immunoglobulins for five days. Her neuro- logical status improved along with improvement in serum IgG levels. Repeat CSF examination showed clearance of Enterovirus from CSF.Rituximab can cause profound, sometimes long-term, B-cell deficiency predisposing to severe EV Encepha- litis. Our case report reminds the need to have a high index of suspicion for CNS infections in such patients, and early detection and treatment with IVIg could dramatically improve patient outcomes.