Idiopathic multicentric Castleman disease (iMCD) is a rare and poorly-understood hematologic disorder characterized by lymphadenopathy, systemic inflammation, cytopenias, and life-threatening multi-organ dysfunction. Interleukin-6 (IL-6) inhibition effectively treats approximately one-third of patients. Limited options exist for non-responders, because the etiology, dysregulated cell types, and signaling pathways are unknown. We previously reported three anti-IL-6 non-responders with increased mTOR activation who responded to mTOR inhibition with sirolimus. We investigated mTOR signaling in tissue and serum proteomes from iMCD patients and controls. mTOR activation was increased in the interfollicular space of iMCD lymph nodes (N=26) compared to control lymph nodes by immunohistochemistry (IHC) for pS6, p4EBP1, and p70S6K, known effectors and read-outs of mTORC1 activation. IHC for pS6 also revealed increased mTOR activation in iMCD compared to Hodgkin lymphoma, systemic lupus erythematosus, and reactive lymph nodes, suggesting that the mTOR activation in iMCD is not just a product of lymphoproliferation/inflammatory lymphadenopathy. Further, the degree of mTOR activation in iMCD was comparable to autoimmune lymphoproliferative syndrome, a disease driven by mTOR hyperactivation that responds to sirolimus treatment. Geneset enrichment analysis of serum proteomic data from iMCD patients (n=88) and controls (n=42) showed significantly enriched mTORC1 signaling. Finally, functional studies revealed increased baseline mTOR pathway activation in peripheral monocytes and T-cells from iMCD remission samples compared to healthy controls. IL-6 stimulation augmented mTOR activation in iMCD patients, which was abrogated with JAK1/2 inhibition. These findings support mTOR activation as a novel therapeutic target for iMCD, which is being investigated through a trial of sirolimus (NCT03933904).