TAFRO syndrome, a rare variant of Castleman's disease, is characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly. First-line treatments typically include immunosuppressive therapies such as cyclosporine A and tocilizumab. However, the use of rituximab as a first-line therapeutic agent remains under-reported. Here, we present the case of a 38-year-old female patient who initially exhibited lymphadenopathy and gradually developed the full spectrum of symptoms associated with TAFRO syndrome during her hospital stay. Rituximab, supplemented by prednisolone, was administered as the primary treatment. Over a follow-up period of five months, the patient's condition improved significantly, suggesting a positive therapeutic response. This case highlights the potential efficacy of rituximab as an alternative first-line therapy for TAFRO syndrome, offering a possible treatment option where standard therapeutic agents may not be available, suitable or effective.