Background: Rituximab, an anti-CD20 monoclonal antibody, has been used worldwide as an off-label therapy in patients with multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). Objective: The aim of the present study was to evaluate the efficacy and safety of rituximab in central nervous system demyelinating disorders in the Indian context. Methods: We conducted a retrospective analysis of patients with MS, NMOSD, and myelin oligodendrocyte glycoprotein antibody disease (MOGAD) who were treated with rituximab at a single tertiary care centre in Mumbai. Results: The study enrolled 102 patients (61 MS, 37 NMOSD and 4 MOGAD) from June 2008 to January 2020. Following rituximab therapy, 96.7% of MS, 67% of NMOSD, and 50% of MOGAD patients were free of relapses. The mean annualized relapse rate reduced from 2.17 to 0 for patients with relapsing remitting MS (RRMS), from 0.8 to 0 for secondary progressive MS (SPMS), from 2.5 to 0.14 for NMOSD, and from 3.43 to 1.04 for MOGAD. The median expanded disability status scale improved significantly in RRMS patients, worsened non-significantly in the SPMS group, and remained unchanged in NMOSD and MOGAD patients. On follow-up magnetic resonance imaging, there was a significant reduction in the number of MS patients developing new contrast enhancing lesions or new T2 lesions. Adverse events (infusion reactions or severe infections) occurred in 12 patients. Conclusion: Rituximab is effective and safe in Indian patients with MS and NMOSD.