<p>Idiopathic multicentric Castleman disease (iMCD) is a rare hematologic disorder characterized by a systemic cytokine storm. Interleukin-6 (IL-6) is central to iMCD pathogenesis and IL-6-targeted therapy is the preferred first-line treatment, yet most patients still receive non-anti-IL-6 regimens. We conducted a single-center retrospective study of patients with iMCD to evaluate the clinical utility of serum IL-6 monitoring—at baseline and longitudinally—with particular emphasis on those receiving non-anti-IL-6 therapy. Among 149 patients (660 IL-6 measurements; 76 male/73 female; median age 45 years), 34 received anti-IL-6 therapy and 115 received non-anti-IL-6 therapy. Baseline IL-6 differed across clinical and pathologic subtypes and correlated negatively with hemoglobin and albumin, and positively with platelet count, C-reactive protein (CRP), and immunoglobulin G (IgG). Baseline IL-6 did not predict biochemical response. IL-6 dynamics were uninformative in the anti-IL-6 group; however, in the non-anti-IL-6 group, IL-6 declined significantly after treatment, with greater decreases in responders than in non-responders. Among initial responders, a directional trend toward rising IL-6 levels was observed prior to biochemical PD identification, whereas persistently suppressed IL-6 was observed in sustained remission. Early IL-6 change predicted subsequent biochemical response; at 1 month, a ΔlogIL-6 threshold of − 0.16 achieved 91.7% sensitivity and 92.3% specificity. These findings support serum IL-6 monitoring as a useful tool for response assessment and early prediction in iMCD, especially among patients receiving non-anti-IL-6 therapies.</p>