Background Idiopathic multicentric Castleman disease (iMCD) is a chronic inflammatory condition for which Janus kinase (JAK) inhibition has been hypothesized to be a potential treatment. However, filgotinib, a JAK1 preferential inhibitor, did not show apparent efficacy for iMCD in a clinical trial at eight weeks. This study aimed to compare the serum cytokine and chemokine profiles of patients treated with filgotinib with those of patients treated with tocilizumab to speculate why filgotinib was not effective at eight weeks. Methods This study included five patients treated with filgotinib who participated in a phase Ib single-arm clinical trial of filgotinib for iMCD and five tocilizumab-treated patients whose data were collected retrospectively. Serum levels of 41 cytokines/chemokines before and after treatment were measured. Results The tocilizumab group showed improvement in C-reactive protein, hemoglobin, and albumin levels after treatment while the filgotinib group showed no changes in these markers. The tocilizumab group showed significant changes in 12 cytokines/chemokines from baseline to after treatment, whereas the filgotinib group showed only a decrease in IL-18 and IL-27 levels. After treatment, significant differences were observed between the two groups for 10 cytokines/chemokines. Five cytokines (FGF-2, IL-4, IL-6, TNF-β, and VEGF-A) showed significant changes after tocilizumab treatment and differences between the tocilizumab and filgotinib groups after treatment. Conclusion This study identified FGF-2, IL-4, IL-6, TNF-β, and VEGF-A as potential factors that could explain the lack of apparent efficacy of filgotinib in iMCD treatment at eight weeks. These findings may contribute to future drug development for iMCD.