Background: Pemphigus is a group of potentially fatal autoimmune mucocutaneous blistering diseases. Rituximab (RTX) is a chimeric anti-CD20 (anti-cluster of differentiate 20) monoclonal antibody being increasingly used and becoming the first-line therapy in the management of pemphigus. Aims and Objectives: This was an observational study to evaluate the efficacy and safety of rituximab in patients of pemphigus vulgaris (PV) who either did not respond or relapsed after conventional therapeutic regimens and in treatment naive pemphigus patients. Materials and Methods: The study included pemphigus patients coming to our immunobullous clinic who did not respond to conventional therapy or relapsed after receiving conventional therapy as well as fresh cases between January 2019 and October 2021. All enrolled patients received two doses of rituximab (1 gram in each) as intravenous infusions two weeks apart as per the rheumatoid arthritis protocol. The efficacy and safety were evaluated by assessing pemphigus area and activity score (PAAS) before and after the therapy, clinical response, and any adverse events during follow-up. Results: Sixteen (ten males and six females) patients were included in the study. The age of these patients ranged from 27 to 60 years, with a mean of 43.8 ± 9.8 years. There were 15 (93.75%) patients with PV (14 mucocutaneous type and 01 mucosal) and one (6.25%) with pemphigus foliaceus. Among these patients, nine (56.25%) were relapse cases, four (25%) were non-responders, and three (18.75%) were fresh cases who received rituximab as first-line therapy. Fourteen (87.5%) patients reached complete remission off therapy over a median time of 6.36 months (ranging from 18 weeks to 35 weeks). Rituximab was well-tolerated by our patients, and no serious adverse events were observed. The main limitation of our study was the small sample size and the lack of a comparison group. Conclusion: Rituximab is a safe and effective treatment for pemphigus.