© 2017, © 2017 Japan College of Rheumatology. Objectives: Serum soluble interleukin-2 (IL-2) receptor (sIL-2R) might reflect disease activity in immunoglobulin G4-related disease (IgG4-RD). We aimed to elucidate the clinical significance of blood markers, including sIL-2R, in patients with IgG4-RD. Methods: We enrolled 59 patients with IgG4-RD and investigated the association between blood markers (white blood cells, C-reactive protein, sIL-2R, IgG, IgG4, IgE, total hemolytic complement), and clinical indices. Results: At baseline, serum sIL-2R (Rs = 0.532, p <.001) and IgG4 (Rs = 0.545, p <.001) levels showed significant correlation to the number of organs involved. During follow-up period (median, 70 months; range, 7–195 months), 40 patients were treated with corticosteroids. Receiver operating characteristic (ROC) analysis showed that baseline sIL-2R levels most accurately predicted patients requiring glucocorticoid treatment (area under the ROC curve, 0.807). Among the 46 patients who improved, sIL-2R and IgG4 levels decreased in 42 and 41 patients, respectively. Among them, serum sIL-2R levels decreased to a normal range in 42 patients (91%), whereas IgG4 levels normalized in 19 (41%). Conclusion: The serum sIL-2R level is a potential biomarker for IgG4-RD that may reflect the number of involved organs and may predict patients requiring glucocorticoid treatment.