Severe TAFRO-associated idiopathic multicentric Castleman Disease (iMCD-TAFRO) is burdened by adverse prognosis, as systemic inflammation can lead to multi-organ failure and patient death. Relapsed/refractory cases management remains challenging, as few therapeutic options exist for siltuximab non-responders. This report detailed a 47-year-old male patient with severe relapsed/refractory iMCD-TAFRO successfully treated with ruxolitinib as salvage therapy in a unique combination setting alongside tocilizumab. The case highlighted ruxolitinib effectiveness and excellent tolerability in the iMCD-TAFRO setting and provided insights into new targeted therapy combination strategies. Future studies are needed to determine the role and of JAK inhibitors in the treatment of iMCD-TAFRO.